Pyrazolopyridinyl pyrimidine therapeutic compounds

ABSTRACT

The present invention provides compounds of formula (I): 
                         
pharmaceutical compositions containing the same, processes for preparing the same and their use as pharmaceutical agents.

CROSS REFERENCES TO RELATED APPLICATIONS

This application is a 371 Application of PCT/US02/06552, filed 5 Mar.2002, which claims priority to U.S. Application Ser. No. 60/274,297,filed 8 Mar. 2001.

BACKGROUND OF THE INVENTION

The present invention relates to novel compounds, pharmaceuticalformulations comprising these compounds, and the use of these compoundsin therapy. More particularly, the present invention relates tocompounds for the prophylaxis and treatment of herpes viral infections.

Of the DNA viruses, those of the herpes group are the sources of themost common viral illnesses in man. The group includes herpes simplexvirus types 1 and 2 (HSV), varicella zoster virus (VZV), cytomegalovirus(CMV), Epstein-Barr virus (EBV), human herpes virus type 6 (HHV-6),human herpes virus type 7 (HHV-7) and human herpes virus type 8 (HHV-8).HSV-1 and HSV-2 are some of the most common infectious agents of man.Most of these viruses are able to persist in the host's neural cells;once infected, individuals are at risk of recurrent clinicalmanifestations of infection which can be both physically andpsychologically distressing.

Herpes simplex viruses (HSV-1 and -2) are the causative agents of herpeslabialis and genital herpes. HSV infection is often characterised byextensive and debilitating lesions of the skin, mouth and/or genitals.Primary infections may be subclinical although tend to be more severethan infections in individuals previously exposed to the virus. Ocularinfection by HSV can lead to keratitis or cataracts thereby endangeringthe host's sight. Infection in the new-born, in immunocompromisedpatients or penetration of the infection into the central nervous systemcan prove fatal. In the US alone, 40 million individuals are infectedwith HSV-2, a number that is expected to increase to 60 million by 2007.Over 80% of individuals infected with HSV-2 are unaware they carry andspread the virus, and of those diagnosed less than 20% received oraltherapies. The net result is that less than 5% of the infectedpopulation are treated. Likewise of the 530 million individualsworldwide who carry HSV-1, 81% of the symptomatic population remainuntreated. No cure exists for HSV infection, and once infected,individuals carry the virus for life in a dormant state. Reactivation ofthe virus from latency occurs periodically and may be triggered bystress, environmental factors, and/or suppression of the host immunesystem. Currently, the use of nucleoside analogs such as valaciclovir(VALTREX®) and aciclovir (ZOVIRAX®) is the standard of care for managinggenital herpes virus outbreaks.

Varacella zoster virus (VZV) (also know as herpes zoster virus) is aherpes virus which causes chickenpox and shingles. Chickenpox is theprimary disease produced in a host without immunity, and in youngchildren is usually a mild illness characterised by a vesicular rash andfever. Shingles or zoster is the recurrent form of the disease whichoccurs in adults who were previously infected with VZV. The clinicalmanifestations of shingles are characterised by neuralgia and avesicular skin rash that is unilateral and dermatomal in distribution.Spread of inflammation may lead to paralysis or convulsions. Coma canoccur if the meninges become affected. VZV is of serious concern inpatients receiving immunosuppressive drugs for transplant purposes orfor treatment of malignant neoplasia and is a serious complication ofAIDS patients due to their impaired immune system.

In common with other herpes viruses, infection with CMV leads to alifelong association of virus and host. Congenital infection followinginfection of the mother during pregnancy may give rise to clinicaleffects such as death or gross disease (microcephaly,hepatosplenomegaly, jaundice, mental retardation), retinitis leading toblindness or, in less severe forms, failure to thrive, andsusceptibility to chest and ear infections. CMV infection in patientswho are immunocompromised for example as a result of malignancy,treatment with immunosuppressive drugs following transplantation orinfection with Human Immunodeficiency Virus, may give rise to retinitis,pneumonitis, gastrointestinal disorders and neurological diseases. CMVinfection is also associated with cardiovascular diseases and conditionsincluding restenosis and atherosclerosis.

The main disease caused by EBV is acute or chronic infectiousmononucleosis (glandular fever). Examples of other EBV or EBV associateddiseases include lymphoproliferative disease which frequently occurs inpersons with congenital or acquired cellular immune deficiency, X-linkedlymphoproliferative disease which occurs namely in young boys,EBV-associated B-cell tumours, Hodgkin's disease, nasopharyngealcarcinoma, Burkitt lymphoma, non-Hodgkin lymphoma, thymomas and oralhairy leukoplakia. EBV infections have also been found in associationwith a variety of epithelial-cell-derived tumours of the upper and lowerrespiratory tracts including the lung. EBV infection has also beenassociated with other diseases and conditions including chronic fatiguesyndrome, multiple sclerosis and Alzheimer's disease.

HHV-6 has been shown to be a causative agent of infantum subitum inchildren and of kidney rejection and interstitial pneumonia in kidneyand bone marrow transplant patients, respectively, and may be associatedwith other diseases such as multiple sclerosis. There is also evidenceof repression of stem cell counts in bone marrow transplant patients.HHV-7 is of undetermined disease aetiology.

Hepatitis B virus (HBV) is a viral pathogen of world-wide majorimportance. The virus is aetiologically associated with primaryhepatocellular carcinoma and is thought to cause 80% of the world'sliver cancer. Clinical effects of infection with HBV range fromheadache, fever, malaise, nausea, vomiting, anorexia and abdominalpains. Replication of the virus is usually controlled by the immuneresponse, with a course of recovery lasting weeks or months in humans,but infection may be more severe leading to persistent chronic liverdisease outlined above.

BRIEF SUMMARY OF THE INVENTION

According to a first aspect of the invention there is provided thecompound of formula (I):

wherein:

-   R¹ is selected from the group consisting of halo, —NR⁷R⁸, Ay,    —NR⁷Ay, Het, —NHR¹⁰Het, NHHet and —NHR¹⁰Ay;    -   each R⁷ and R⁸ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        alkenyl, cycloalkenyl, —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹,        —R¹⁰C(O)R⁹, —C(O)R⁹, —C(O)R¹⁰Ay, —C(O)R¹⁰Het, —CO₂R⁹, —R¹⁰CO₂R⁹,        —C(O)NR⁹R¹¹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(O)Ay, —R¹⁰C(O)Het,        —C(S)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹,        —R¹⁰NHC(O)R¹⁰Het, —R¹⁰NHC(O)R¹⁰CO₂R⁹, —R¹⁰NHC(NCO₂R⁹)NHCO₂R⁹,        —R¹⁰NHC(O)NHSO₂R⁹, —R¹⁰NHC(O)NHSO₂Ay, —R¹⁰NHC(O)NHSO₂Het,        —R¹⁰C(NH)NR⁹R¹¹, —C(NH)NR⁹R¹¹, —SO₂NR⁹R¹¹, —R¹⁰SO₂NR⁹R¹¹,        —R¹⁰NHSO₂R⁹, —SO₂R¹⁰, —R¹⁰SO₂R¹⁰, —R¹⁰NHCOR⁹, —R¹⁰SO₂NHCOR⁹,        —R¹⁰NHP(O)(OR⁹)₂, —R¹⁰OP(O)(OR⁹)₂ and —R¹⁰OP(O)(OR¹⁰Ay)₂;    -   each R⁹ and R¹¹ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        —R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) where w is 1–10, and        —R¹⁰NR¹⁰R¹⁰;    -   each R¹⁰ is the same or different and is independently selected        from the group consisting of alkyl, cycloalkyl, alkenyl,        cycloalkenyl, and alkynyl;    -   Ay is aryl;    -   Het is a 5- or 6-membered heterocyclic or heteroaryl group;-   R² is selected from the group consisting of halo, alkyl, cycloalkyl,    alkenyl, cycloalkenyl, —NR⁷R⁸, —OR⁷, —OAy, —S(O)_(n)R⁹, —S(O)_(n)Ay,    —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, Ay, Het, —NHHet, —NHR¹⁰Het, —OHet and    —OR¹⁰Het;-   n is 0, 1 or 2;-   Y is N or CH;-   R³ and R⁴ are the same or different and are each independently    selected from the group consisting of H, halo, alkyl, cycloalkyl,    alkenyl, Ay, —OR⁷, —OAy, —R¹⁰OR⁷, —R¹⁰OAy, —NR⁷R⁸, —NR⁷Ay,    —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —C(O)R⁷, —C(O)Ay, —CO₂R⁷, —CO₂Ay, —SO₂NHR⁹,    Het, —NHHet and NHR¹⁰Het;-   q is 0, 1, 2, 3, 4 or 5; and-   each R⁵ is the same or different and is independently selected from    the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, —R¹⁰cycloalkyl, Ay, —NHR¹⁰Ay, Het, —NHHet, —NHR¹⁰Het,    —OR⁷, —OAy, —OHet, —R¹⁰OR⁹, —NR⁷R⁸, —NR⁷Ay, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay,    —R¹⁰C(O)R⁹, —C(O)R⁹, —CO₂R⁹, —R¹⁰CO₂R⁹, —C(O)NR⁷R⁸, —C(O)Ay,    —C(O)NR⁷Ay, —C(O)Het, —C(O)NHR¹⁰Het, —R¹⁰C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹,    —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —C(NH)NR⁷R⁸, —R¹⁰C(NH)NR⁹R¹¹,    —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂R⁹,    —S(O)_(n)R⁹, cyano, nitro and azido; or-    two adjacent R⁵ groups together with the atoms to which they are    attached form a C₅₋₆ cycloalkyl or aryl;-   wherein when q is 1 and R⁵ is in the para position, R⁵ is not halo;-   wherein when Y is CH, R³ is not —NR⁷Ay;-   and pharmaceutically acceptable salts, solvates and physiologically    functional derivatives thereof.

In another aspect of the invention there is provided a pharmaceuticalcomposition comprising a compound of formula (I). In one embodiment, thepharmaceutical composition further comprises a pharmaceuticallyacceptable carrier or diluent. In one embodiment, the pharmaceuticalcomposition further comprises an antiviral agent selected from the groupconsisting of aciclovir and valacicilovir.

In a third aspect of the invention, there is provided a method for theprophylaxis or treatment of herpes viral infections in an animal. Themethod comprises administering to the animal a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt, solvate or physiologically functional derivative thereof. Theherpes viral infection can be any of herpes simplex virus 1, herpessimplex virus 2, cytomegalovirus, Epstein Barr virus, varacella zostervirus, human herpes virus 6, human herpes virus 7, and human herpesvirus 8.

In a fourth aspect, there is provided a method for the treatment orprophylaxis of conditions or diseases associated with herpes viralinfections in an animal. The method comprises administering to theanimal a therapeutically effective amount of a compound of formula (I)or a salt, solvate or physiologically functional derivative thereof.

In another aspect, there is provided a process for preparing thecompounds of formula (I) wherein Y is N, R² is selected from the groupconsisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, Ay, —NR⁷R⁸,—OR⁷, —OAy, —S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, Het, —NHHet,—NHR¹⁰Het, —OHet, and —OR¹⁰Het; and R³ and R⁴ are H. The processcomprises reacting a compound of formula (IX):

with an amine of formula (X):

In another aspect, the present invention provides a process forpreparing the compounds of formula (I) wherein Y is N, R² is selectedfrom the group consisting of H, alkyl, cycloalkyl, alkenyl,cycloalkenyl, Ay, —NR⁷R⁸, —OR⁷, —OAy, —S(O)_(n)R⁹, —S(O)_(n)Ay,—R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, Het, —NHHet, —NHR¹⁰Het, —OHet, and —OR¹⁰Het; R³ isselected from the group consisting of H, alkyl, cycloalkyl, alkenyl,—R¹⁰OR⁷, —R¹⁰OAy, —NR⁷R⁸ where R⁷ and R⁸ are not H, Ay, —NR⁷Ay where R⁷is not H, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —C(O)R⁷, —C(O)Ay, —CO₂R⁷, —CO₂Ay,—SO₂NHR⁹ and Het; and R⁴ is H. The process comprises reacting a compoundof formula (XVI):

with an amine of formula (X):

In another aspect, the present invention provides a process forpreparing the compounds of formula (I) wherein Y is N and R² is selectedfrom the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl,Ay, —NR⁷R⁸, —OR⁷, —OAy, —S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸, R¹⁰NR⁷R⁸,Het, —NHHet, —NHR¹⁰Het, —OHet, and —OR¹⁰Het. The process comprises thesteps of:

-   a) reacting a compound of formula (XX):

-    with an amine of formula (X):

-    to prepare an intermediate compound; and-   b) oxidizing the intermediate compound.

In another aspect, the present invention provides a process forpreparing the compounds of formula (I). The process comprises reacting acompound of formula (XXII):

with a compound of formula XXIV:

wherein X¹ is chloro, bromo or iodo; and M² is selected from the groupconsisting of —B(OH)₂, —B(ORa)₂, —B(Ra)₂, —Sn(Ra)₃, Zn-halide, ZnRa, andMg-halide, where Ra is alkyl or cycloalkyl and halide is halo.

In another aspect, the present invention provides a process forpreparing compounds of formula (VI):

wherein when q is 1 and R⁵ is in the para position, R⁵ is not halo.

The process comprises rearranging the compound of formula (V):

As another aspect, the present invention provides a process forpreparing compounds of formula (XXII-B)

wherein R¹³ is selected from the group consisting of —NR⁷R⁸, —NR⁷Ay,Het, —NHR¹⁰Het, —NHHet and —NHR¹⁰Ay and wherein when q is 1 and R⁵ is inthe para position, R⁵ is not halo. The process comprises reacting acompound of formula (XXII-A):

with a compound of formula H—R¹³.

In another aspect, the present invention provides a radiolabeledcompound of formula (I) or a pharmaceutically acceptable salt, solvateor physiologically functional derivative thereof. In one embodiment, thepresent invention provides a tritiated compound of formula (I) or apharmaceutically acceptable salt, solvate or physiologically functionalderivative thereof. In another aspect, the present invention provides abiotinylated compound of formula (I) or a pharmaceutically acceptablesalt, solvate or physiologically functional derivative thereof.

In another aspect, the present invention provides a compound of formula(I) for use in therapy.

In yet another aspect, the present invention provides the use of acompound of formula (I) for the prophylaxis or treatment of herpes viralinfections.

In yet another aspect, the present invention provides a compound offormula (I) for the prophylaxis or treatment of conditions or diseasesassociated with herpes viral infections in an animal.

In yet another aspect, the present invention provides the use of acompound of formula (I) for the preparation of a medicament for theprophylaxis or treatment of herpes viral infections in animals,preferrably humans.

In yet another aspect, the present invention provides the use of acompound of formula (I) for the preparation of a medicament for thetreatment or prophylaxis of diseases or conditions associated withherpes viral infections in animals, preferrably humans.

In yet another aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of formula (I) for use in theprophylaxis or treatment of herpes viral infections in an animal.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, “a compound of the invention” means a compound offormula (I) or a pharmaceutically acceptable salt, solvate, orphysiologically functional derivative thereof. Similarly, with respectto isolatable intermediates such as compounds of formula (VI), (IX),(XVI), (XX), (XXII) and (XXII-B), the phrase “a compound of formula(number)” means a compound having that formula and pharmaceuticallyacceptable salts, solvates and physiologically functional derivativesthereof.

As used herein, the terms “alkyl” and “alkylene” refer to straight orbranched hydrocarbon chains containing from 1 to 8 carbon atoms.Examples of “alkyl” as used herein include, but are not limited to,methyl, ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopropyl, andtert-butyl. Examples of “alkylene” as used herein include, but are notlimited to, methylene, ethylene, propylene, butylene, and isobutylene.“Alkyl also includes substituted alkyl (alkylene). The alkyl groups maybe optionally substituted one or more times with a substituent selectedfrom the group consisting of mercapto, nitro, cyano and halo.Trihalomethyl, such as trifluoromethyl is one particularly preferredalkyl group.

As used herein, the term “cycloalkyl” refers to a non-aromaticcarbocyclic ring having from 3 to 8 carbon atoms and no carbon-carbondouble bonds. “Cycloalkyl” includes by way of example cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.“Cycloalkyl” also includes substituted cycloalkyl. The cycloalkyl mayoptionally be substituted on an available carbon with one or moresubstituents selected from the group consisting of mercapto, nitro,cyano, halo, and alkyl.

As used herein, the term “alkenyl” refers to straight or branchedhydrocarbon chains containing from 2 to 8 carbon atoms and at least oneand up to three carbon-carbon double bonds. Examples of “alkenyl” asused herein include, but are not limited to ethenyl and propenyl.“Alkenyl” also includes substituted alkenyl. The alkenyl groups mayoptionally be substituted on an available carbon with one or moresubstituents selected from the group consisting of mercapto, nitro,cyano, halo, and alkyl.

As used herein, the term “cycloalkenyl” refers to refers to anon-aromatic carbocyclic ring having from 3 to 8 carbon atoms (unlessotherwise specified) and up to 3 carbon-carbon double bonds.“Cycloalkenyl” includes by way of example cyclobutenyl, cyclopentenyland cyclohexenyl. “Cycloalkenyl” also includes substituted cycloalkenyl.The cycloalkenyl may optionally be substituted on an available carbonwith one or more substituents selected from the group consisting ofmercapto, nitro, cyano, halo, and alkyl.

As used herein, the term “alkynyl” refers to straight or branchedhydrocarbon chains containing from 2 to 8 carbon atoms and at least oneand up to three carbon-carbon triple bonds. Examples of “alkynyl” asused herein include, but are not limited to ethynyl and propynyl.“Alkynyl” also includes substituted alkynyl. The alkynyl groups mayoptionally be substituted on an available carbon with one or moresubstituents selected from the group consisting of mercapto, nitro,cyano, and halo.

The term “halo” or “halogen” refers to the elements fluorine, chlorine,bromine and iodine.

The term “aryl” refers to monocyclic carbocyclic groups and fusedbicyclic carbocyclic groups having from 5 to 12 carbon atoms and havingat least one aromatic ring. Examples of particular aryl groups includebut are not limited to phenyl, and naphthyl. “Aryl” also includessubstituted aryl. Aryl groups may be optionally substituted on anavailable carbon with one or more substituents selected from the groupconsisting of halo, alkyl (including perhaloalkyl), alkenyl, cycloalkyl,cycloalkenyl, alkoxy, cycloalkoxy, amino, mercapto, hydroxy,alkylhydroxy, alkylamine, cycloalkylamine, carboxy, carboxamide,sulfonamide, Het, amidine, cyano, nitro and azido. Preferred aryl groupsaccording to the invention include but are not limited to phenyl andsubstituted phenyl.

The term “heterocyclic” (or “heterocycle”) refers to a monocyclicsaturated or unsaturated non-aromatic groups and fused bicyclicnon-aromatic groups, having the specified number of members (totalcarbon atoms and heteroatoms) and containing 1, 2, 3 or 4 heteroatomsselected from N, O and S. Examples of particular heterocyclic groupsinclude but are not limited to tetrahydrofuran, dihydropyran,tetrahydropyran, pyran, oxetane, thietane, 1,4-dioxane, 1,3-dioxane,1,3-dioxalane, piperidine, piperazine, tetrahydropyrimidine,pyrrolidine, morpholine, thiomorpholine, thiazolidine, oxazolidine,tetrahydrothiopyran, tetrahydrothiophene, and the like. “Heterocyclic”also refers to substituted heterocyclic. The heterocyclic group may beoptionally substituted on any available carbon or heteroatom, with oneor more substituents selected from the group consisting of halo, alkyl(including perhaloalkyl), alkenyl, cycloalkyl, cycloalkenyl, alkoxy,cycloalkoxy, amino, mercapto, hydroxy, alkylhydroxy, alkylamine,cycloalkylamine, carboxy, carboxamide, sulfonamide, Het, amidine, cyano,nitro and azido. Preferred heterocyclic groups according to theinvention include but are not limited to pyrrolidine, piperidine,morpholine, thiomorpholine and piperazine and substituted variantsthereof.

The term “heteroaryl” refers to aromatic monocyclic groups and aromaticfused bicyclic groups having the specified number of members (totalcarbon atoms and heteroatoms) and containing 1, 2, 3, or 4 heteroatomsselected from N, O and S. Examples of particular heteroaryl groupsinclude but are not limited to furan, thiophene, pyrrole, imidazole,pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole,thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine,quinoline, isoquinoline, benzofuran, benzothiophene, indole, andindazole. “Heteroaryl” also includes substituted heteroaryl. Theheteroaryl group may be optionally substituted on any available carbonor heteroatom with one or more substituents selected from the groupconsisting of halo, alkyl (including perhaloalkyl), alkenyl, cycloalkyl,cycloalkenyl, alkoxy, cycloalkoxy, amino, mercapto, hydroxy,alkylhydroxy, alkylamine, cycloalkylamine, carboxy, carboxamide,sulfonamide, Het, amidine cyano, nitro and azido. Preferred heteroarylgroups according to the invention include but are not limited topyridine, furan, thiophene, pyrrole, imidazole, pyrazole, and pyrimidineand substituted variants thereof.

As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both event(s)which occur and events that do not occur.

The present invention provides compounds of formula (I):

wherein:

-   R¹ is selected from the group consisting of halo, —NR⁷R⁸, Ay,    —NR⁷Ay, Het, —NHR¹⁰Het, —NHHet and —NHR¹⁰Ay;    -   each R⁷ and R⁸ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        alkenyl, cycloalkenyl, —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹,        —R¹⁰C(O)R⁹, —C(O)R⁹, —C(O)R¹⁰Ay, —C(O)R¹⁰Het, —CO₂R⁹, —R¹⁰CO₂R⁹,        —C(O)NR⁹R¹¹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰OC(O)Ay, —R¹⁰C(O)Het,        —C(S)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹,        —R¹⁰NHC(O)R¹⁰Het, —R¹⁰NHC(O)R¹⁰CO₂R⁹, —R¹⁰NHC(NCO₂R⁹)NHCO₂R⁹,        —R¹⁰NHC(O)NHSO₂R⁹, —R¹⁰NHC(O)NHSO₂Ay, —R¹⁰NHC(O)NHSO₂Het,        —R¹⁰C(NH)NR⁹R¹¹, —C(NH)NR⁹R¹¹, —SO₂NR⁹R¹¹, —R¹⁰SO₂NR⁹R¹¹,        —R¹⁰NHSO₂R⁹, —SO₂R¹⁰, —R¹⁰SO₂R¹⁰, —R¹⁰NHCOR⁹, —R¹⁰SO₂NHCOR⁹,        —R¹⁰NHP(O)(OR⁹)₂, —R¹⁰OP(O)(OR⁹)₂ and —R¹⁰OP(O)(OR¹⁰Ay)₂;    -   each R⁹ and R¹¹ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        —R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) wherein w is 1–10, and        —R¹⁰NR¹⁰R¹⁰;    -   each R¹⁰ is the same or different and is independently selected        from the group consisting of alkyl, cycloalkyl, alkenyl,        cycloalkenyl and alkynyl;    -   Ay is aryl;    -   Het is a 5- or 6-membered heterocyclic or heteroaryl group;-   R² is selected from the group consisting of halo, alkyl, cycloalkyl,    alkenyl, cycloalkenyl, —NR⁷R⁹, —OR⁷, —OAy, —S(O)_(n)R⁹, —S(O)_(n)Ay,    —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, Ay, Het, —NHHet, —NHR¹⁰Het, —OHet and    —OR¹⁰Het;-   n is 0, 1 or 2;-   Y is N or CH;-   R³ and R⁴ are the same or different and are each independently    selected from the group consisting of H, halo, alkyl, cycloalkyl,    alkenyl, Ay, —OR⁷, —OAy, —R¹⁰OR⁷, —R¹⁰OAy, —NR⁷R⁸, —NR⁷Ay,    —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —C(O)R⁷, —C(O)Ay, —CO₂R⁷, —CO₂Ay, —SO₂NHR⁹,    Het, —NHHet and —NHR¹⁰Het; and-   q is 0, 1, 2, 3, 4 or 5; and-   each R⁵ is the same or different and is independently selected from    the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, —R¹⁰cycloalkyl, Ay, —NHR¹⁰Ay, Het, —NHHet, —NHR¹⁰Het,    —OR⁷, —OAy, —OHet, —R¹⁰OR⁹, —NR⁷R⁹, —NR⁷Ay, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay,    —R¹⁰C(O)R⁹, —C(O)R⁹, —CO₂R⁹, —R¹⁰CO₂R⁹, —C(O)NR⁷R⁸, —C(O)Ay,    —C(O)NR⁷Ay, —C(O)Het, —C(O)NHR¹⁰Het —R¹⁰C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹,    —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay,    —R¹⁰C(NH)NR⁹R¹¹, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰SO₂NHCOR⁹,    —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂R⁹, —S(O)_(n)R⁹, cyano, nitro and azido; or-    two adjacent R⁵ groups together with the atoms to which they are    bonded form a C₅₋₆ cycloalkyl or aryl;-   wherein when q is 1 and R⁵ is in the para position, R⁵ is not halo;    and-   wherein when Y is CH, R³ is not —NR⁷Ay; and-   pharmaceutically acceptable salts, solvates and physiologically    functional derivatives thereof.

Preferred compounds of formula (I) include those compounds definedwherein at least one of R¹ and R² contains an aryl, heterocyclic orheteroaryl moiety. The groups Ay, —NR⁷Ay, Het, —NHR¹⁰Het, NHHet,—NHR¹⁰Ay, —OAy, —S(O)_(n)Ay, R¹⁰NR⁷Ay, —OHet and —OR¹⁰Het are groupscontaining an aryl, heterocyclic or heteroaryl moieties. In anotherembodiment, preferred compounds of the present invention include thosecompounds defined wherein at least one of R¹ and R² contain aheterocyclic or heteroaryl moiety such as Het, —NHHet, —NHR¹⁰Het, —OHet,and —OR¹⁰Het.

Another preferred class of compounds of formula (I) include thosecompounds defined wherein neither R¹ nor R² contain an aryl,heterocyclic or heteroaryl moiety. In such embodiments, R¹ is preferably—NR⁷R⁸, and R² is preferably selected from the group consisting of H,halo, alkyl, cycloalkyl, alkenyl, cycloalkenyl, —NR⁷R⁸, —OR⁷,—S(O)_(n)R⁹, and —R¹⁰NR⁷R⁸. More particularly preferred compoundsinclude those defined wherein neither R¹ nor R² contain a heterocyclicor heteroaryl moiety but may contain an aryl moiety.

In another embodiment, the compounds of formula (I) include thosecompounds defined where at least one of R³ and R⁴ contain a heterocyclicor heteroaryl moiety. A further embodiment includes those compounds offormula (I) where neither R³ nor R⁴ contain a heterocyclic or heteroarylmoiety.

Another class of compounds of formula (I) includes those compoundsdefined wherein at least one R⁵ group contains an aryl, heterocyclic orheteroaryl moiety (preferably a heterocyclic or heteroaryl moiety) andtwo adjacent R⁵ groups together with the atoms to which they are bondeddo not form a C₅₋₆ cycloalkyl or aryl. Another class of compounds offormula (I) includes those compounds defined wherein q is 3, 4 or 5, atleast one R⁵ group contains an aryl, heterocyclic or heteroaryl moiety(preferably a heterocyclic or heteroaryl moiety) and two adjacent R⁵groups together with the atoms to which they are bonded form a C₅₋₆cycloalkyl or aryl. Another class of compounds of formula (I) includesthose compounds defined where no R⁵ group contains an aryl, heterocyclicor heteroaryl moiety (or in one embodiment no R⁵ group contains aheterocyclic or heteroaryl moeity) and two adjacent R⁵ groups togetherwith the atoms to which they are bonded do not form a C₅₋₆ cycloalkyl oraryl. Another class of compounds of formula (I) includes those compoundsdefined wherein q is 2, 3, 4 or 5, no R⁵ group contains an aryl,heterocyclic or heteroaryl moiety (or in one embodiment no R⁵ groupcontains a heterocyclic or heteroaryl moiety) and two adjacent R⁵ groupstogether with the atoms to which they are bonded form a C₅₋₆ cycloalkylor aryl.

In one preferred class of compounds of formula (I), Y is CH. In anotherpreferred class of compounds of formula (I), Y is N.

Preferably, R¹ is selected from the group consisting of —NR⁷R⁸, Ay,—NR⁷Ay, Het, —NHR¹⁰Het, —NHHet, and —NHR¹⁰Ay, or any subset thereof.More preferably, R¹ is selected from the group consisting of —NR⁷R⁸,Het, —NHR¹⁰Het and —NHHet, or any subset thereof. Particularly preferredcompounds of formula (I) are defined wherein R¹ is —NR⁷R⁸ or Het.

In one preferred embodiment, R¹ is selected from the group consisting of—NH₂, —NH-alkyl, —NH-cycloalkyl, —N(alkyl)(alkyl), Het and —NHAy, or anysubset thereof. More preferably, R¹ is selected from the groupconsisting of —NH-alkyl, —NH-cycloalkyl and pyrrolidone or any subsetthereof.

Specific examples of some prefered R¹ groups are selected from the groupconsisting of —NH₂, —NH-methyl, —N(CH₃)₂, —NH-cyclopentyl,—NH-cyclopropyl, —NH-isopropyl, —NH-butyl, —NH-phenyl and pyrrolidine,or any subset thereof.

R² is preferably selected from the group consisting of —NR⁷R⁸, Ay, —OR⁷,—OAy, —S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, Het, —NHR¹⁰Het,—NHHet, —OHet and —OR¹⁰Het, or any subset thereof. More preferably, R²is selected from the group consisting of —NR⁷R⁸, Het, —NHHet and—NHR¹⁰Het, or any subset thereof. Particularly preferred compounds offormula (I) are defined where R² is selected from the group consistingof —NR⁷R⁸ and Het.

In one preferred embodiment, R² is selected from the group consisting of—NH₂, —NH-alkyl, —NH-cycloalkyl, —N(alkyl)(alkyl) and Het, or any subsetthereof. More preferably, R² is selected from the group consisting of—NH-alkyl and —NH-cycloalkyl, or any subset thereof.

Specific examples of some preferred R² groups are selected from thegroup consisting of —NH₂, —NH-methyl, —NH-ethyl, —NH-cyclopentyl,—NH-cyclopropyl, —NH-isopropyl, —NH-butyl and pyrrolidine, or any subsetthereof.

Preferably, R⁷ and R⁸ are each the same or different and areindependently selected from the group consisting of H, alkyl,cycloalkyl, R¹⁰-cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹, —C(O)R⁹, and R¹⁰CO₂R⁹,or any subset thereof. More preferably, R⁷ and R⁸ are each the same ordifferent and are independently selected from the group consisting of H,alkyl, cycloalkyl and R¹⁰-cycloalkyl, or any subset thereof. In oneembodiment, R⁷ and R⁸ are each the same or different and areindependently selected from the group consisting of H, alkyl andcycloalkyl, or any subset thereof.

Preferably R⁹ and R¹¹ are each the same or different and areindependently selected from the group consisting of H, alkyl, cycloalkyland —R¹⁰-cycloalkyl, or any subset thereof. More preferably, R⁹ and R¹¹are each the same or different and are independently selected from thegroup consisting of H and alkyl.

Preferably R¹⁰ is alkyl or cycloalkyl; more preferably alkyl.

R³ is preferably selected from the group consisting of H, halo, alkyl,—OR⁷, —R¹⁰OR⁷, —NR⁷R⁸, —R¹⁰NR⁷R⁸, —CO₂R⁷ and Ay, or any subset thereof.More preferably, R³ is H, halo, alkyl, —OR⁷ and —NR⁷R⁸, or any subsetthereof. Most preferably R³ is H or alkyl. In one embodiment, R³ is H.

R⁴ is preferably H, halo, alkyl, —OR⁷, —R¹⁰OR⁷, —NR⁷R⁸, —R¹⁰NR⁷R⁸,—CO₂R⁷, or any subset thereof. More preferably R⁴ is H, halo, alkyl,—OR⁷ and —NR⁷R⁸, or any subset thereof. Most preferably, R⁴ is H oralkyl. In one embodiment, R⁴ is H.

More particularly, R³ and R⁴ are preferably each independently selectedfrom the group consisting of H, F, Cl, Br, methyl, ethyl, propyl,O-methyl, O-ethyl, O-isopropyl, —CH₂—O—methyl, —NH₂, —NH(alkyl),—N(alkyl)(alkyl), —CH₂—NH₂, CH₂—NH(alkyl), —CH₂—N(alkyl)(alkyl), —CO₂H,—CO₂-methyl and phenyl, or any subset thereof. More preferably, R³and R⁴are each independently selected from the group consisting of H, F, Cl,Br, methyl, ethyl, propyl, O-methyl, O-ethyl, O-isopropyl, —NH₂,—NH(alkyl) and —N(alkyl)(alkyl), or any subset thereof.

Preferably q is 0, 1 or 2. In one embodiment, q is 0. In one preferredembodiment, q is 1. In one embodiment, q is 2 and the two R⁵ groups arebonded two adjacent carbon atoms, and optionally they together with theatoms to which they are bonded form a cycloalkyl or aryl. The phrase“two adjacent R⁵ groups” refers to two R⁵ groups, each bonded toadjacent carbon atoms on the phenyl ring. In the embodiment where twoadjacent R⁵ groups together with the atoms to which they are bonded forma cycloalkyl or aryl group, q is preferably 2, 3, 4 or 5; morepreferably 2.

R⁵ may be in the ortho, meta or para position.

In the embodiments where two adjacent R⁵ groups together with the atomsto which they are attached form a cycloalkyl or aryl group, each R⁵group may be the same or different and is preferably selected from thegroup consisting of alkyl and alkenyl. In one embodiment, two adjacentR⁵ groups are alkyl and together with the atoms to which they areattached, they form a cycloalkyl group such as:

From this example, additional embodiments, including those where twoadjacent R⁵ groups together with the atoms to which they are bonded forman aryl group, can be readily ascertained by those skilled in the art.Preferably, the compounds of formula (I) are defined wherein twoadjacent R⁵ groups together with the atoms to which they are bonded donot form a C₅₋₆ cycloalkyl or aryl group.

Preferably, each R⁵ group is the same or different and is independentlyselected from the group consisting of halo, alkyl, alkenyl, —OR⁷,—CO₂R⁹, —NR⁷R⁸, C(O)NR⁷R⁸, Ay, —NHR¹⁰Ay, Het, —S(O)₂NR⁷R⁸, cyano, nitroand azido, or any subset thereof. More preferably, each R⁵ group is thesame or different and is independently selected from the groupconsisting of halo, alkyl, alkenyl, —OR⁷, —NR⁷R⁸, Ay, Het —S(O)₂NR⁷R⁸,cyano, nitro and azido, or any subset thereof. Most preferably, each R⁵group is the same or different and is independently selected from thegroup consisting of halo, —OR⁷, NR⁷R⁸, alkyl, and cyano, or any subsetthereof. In particular, preferred embodiments of the compounds offormula (I) are defined where R⁵ is selected from the group consistingof halo (e.g., fluoro, chloro or bromo), alkyl (e.g., methyl), O-alkyl(e.g., O-methyl, O-isobutyl, and

O-allyl, cyano, —NH—CH₃, —N(CH₃)₂, nitro and azido or any subsetthereof.

It is to be understood that the present invention includes allcombinations and subsets of the particular and preferred groups definedhereinabove.

Preferred compounds of formula (I) include but are not limited to:

-   N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)-pyrazolo[1,5-a]pyridin-7-amine,-   N-Cyclopentyl-4-[2-(4-methoxyphenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine,-   4-[2-(4-Methoxyphenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine,-   4-{7-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo-[1,5-a]pyridin-2-yl}phenol,-   4-[3-[2-(Cyclopentylamino)-4-pyrimidinyl]-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenol,-   4-[3-(2-Amino-4-pyrimidinyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenol,-   2-[4-(Allyloxy)phenyl]-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo-[1,5-a]pyridin-7-amine,-   Ethyl    (4-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]-pyrazolo[1,5-a]pyridin-2-yl}phenoxy)acetate,-   2-(4-Butoxyphenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-pyrazolo[1,5-a]pyridin-7-amine,-   N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-isobutoxyphenyl)pyrazolo-[1,5-a]pyridin-7-amine,-   N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[4-(cyclopropyl-methoxy)-phenyl]pyrazolo[1,5-a]pyridin-7-amine,-   2-[4-(Cyclobutylmethoxy)phenyl]-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine,-   N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-phenoxyphenyl)-pyrazolo[1,5-a]pyridin-7-amine,-   2-[1,1′-Biphenyl]-4-yl-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]pyrazolo-[1,5-a]pyridin-7-amine,-   N-{4-[2-(4-Aminophenyl)-7-(butylamino)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-butylamine,-   N-Butyl-3-[2-(butylamino)-4-pyrimidinyl]-2-[4-(cyclohexylamino)phenyl]-pyrazolo[1,5-a]pyridin-7-amine,-   N-Butyl-3-[2-(butylamino)-4-pyrimidinyl]-2-(4-isopropenylphenyl)-pyrazolo[1,5-a]pyridin-7-amine,-   2-(4-Anilinophenyl)-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine,-   2-(4-Anilinophenyl)-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]-N-phenylpyrazolo[1,5-a]pyridin-7-amine,-   2-{4-[Bis(cyclopropylmethyl)amino]phenyl}-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine,-   N-Butyl-3-[2-(butylamino)-4-pyrimidinyl]-2-{4-[(cyclopropylmethyl)amino]phenyl}-pyrazolo[1,5-a]pyridin-7-amine,-   N-Butyl-3-[2-(butylamino)-4-pyrimidinyl]-2-[4-(dimethylamino)phenyl]-pyrazolo[1,5-a]pyridin-7-amine,-   2-(2-Bromophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine,-   2-(3-Bromophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine,-   4-[2-(3-Bromophenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine,-   N-[3-(2-Amino-4-pyrimidinyl)-2-(3-bromophenyl)pyrazolo[1,5-a]pyridin-7-yl]-N-cyclopentylamine,-   4-[2-(3-Bromophenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine,-   2-[1,1′-Biphenyl]-3-yl-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo-[1,5-a]pyridin-7-amine,-   4-[2-[1,1′-Biphenyl]-3-yl-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine,-   N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[3-(4-pyridinyl)phenyl]-pyrazolo[1,5-a]pyridin-7-amine,-   N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[3-(3-thienyl)phenyl]pyrazolo-[1,5-a]pyridin-7-amine,-   N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[3-(2-thienyl)-phenyl]pyrazolo[1,5-a]pyridin-7-amine,-   2-(3-Aminophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine,-   N-(3-{7-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenyl)acetamide,-   N-(3-{7-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]-pyrazolo[1,5-a]pyridin-2-yl}phenyl)methanesulfonamide,-   4-[2-(3-Aminophenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine,-   N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-phenylpyrazolo-[1,5-a]pyridin-7-amine,-   3-{(7-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}benzonitrile,-   3-{7-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]-pyrazolo[1,5-a]pyridin-2-yl}benzamide,-   3-{7-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo-[1,5-a]pyridin-2-yl}benzoic    acid,-   N-{4-[2-(3-Bromo-4-methoxyphenyl)-7-(cyclopentylamino)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-cyclopentylamine,-   2-(3-Bromo-4-chlorophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-pyrazolo[1,5-a]pyridin-7-amine,-   2-(3-Amino-4-chlorophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine,-   2-[4-(Benzylamino)phenyl]-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]-pyrazolo[1,5-a]pyridin-7-amine,-   N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-7-amine,-   4-[7-Chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-5,6-dimethyl-2-pyrimidinamine,-   N-cyclopentyl-3-[2-(cyclopentylamino)-5,6-dimethyl-4-pyrimidinyl]-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-7-amine,-   3-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-isopropyl-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-7-amine,-   4-[7-Chloro-2-(3-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine,-   N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(3-methoxyphenyl)-pyrazolo[1,5-a]pyridin-7-amine,-   3-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-isopropyl-2-(3-methoxyphenyl)-pyrazolo[1,5-a]pyridin-7-amine,-   3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(3-methoxyphenyl)-N,N-dimethylpyrazolo-[1,5-a]pyridin-7-amine,-   3-{7-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenol,-   N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[3-(cyclopropylmethoxy)phenyl]pyrazolo[1,5-a]pyridin-7-amine,-   N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(3-fluorophenyl)pyrazolo[1,5-a]pyridin-7-amine,-   2-(3-Chlorophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine,-   N-Cyclopentyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine,-   3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)-N-[2-(4-morpholinyl)ethyl]pyrazolo[1,5-a]pyridin-7-amine,-   3-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-cyclopropyl-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine,-   N-Cyclopentyl-4-[2-(4-methoxyphenyl)-7-(4-morpholinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine,-   3-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-(2-methoxyethyl)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine,-   N-Cyclopropyl-4-[2-(4-methoxyphenyl)-7-(4-morpholinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine,-   3-[2-(Cyclopropylamino)-4-pyrimidinyl]-N-(2-methoxyethyl)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine,-   3-[2-(Cyclopropylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)-N-[2-(4-morpholinyl)ethyl]pyrazolo[1,5-a]pyridin-7-amine,-   N-Cyclopropyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine,-   4-[3-[2-(Cyclopentylamino)-4-pyrimidinyl]-7-(cyclopropylamino)pyrazolo[1,5-a]pyridin-2-yl]phenol,-   4-{7-(Cyclopentylamino)-3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenol,-   4-{7-(Cyclopropylamino)-3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenol,-   3-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-cyclopropyl-2-[4-(cyclopropylmethoxy)phenyl]pyrazolo[1,5-a]pyridin-7-amine,-   2-[4-(Allyloxy)phenyl]-N-cyclopentyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine,-   N-Cyclopropyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]-2-[4-(cyclopropylmethoxy)phenyl]pyrazolo[1,5-a]pyridin-7-amine,-   2-[4-(Allyloxy)phenyl]-N-cyclopropyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine,-   N-Butyl-3-[2-(butylamino)pyrimidin-4-yl]-2-{4-[(4-methoxybenzyl)amino]phenyl}pyrazolo[1,5-a]pyridin-7-amine,-   N-Butyl-3-[2-(butylamino)pyrimidin-4-yl]-2-(4-morpholin-4-ylphenyl)pyrazolo[1,5-a]pyridin-7-amine,-   2-(3-Bromophenyl)-N-cyclopentyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine,-   2-(3-Bromophenyl)-3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-cyclopropylpyrazolo[1,5-a]pyridin-7-amine,-   2-(3-Bromophenyl)-N-cyclopropyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine,-   Methyl    N-[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]glycinate,-   5-[(3aS,4S,6aR)-2-Oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl]-N-(4-{(7-(butylamino)-3-[2-(butylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-2-yl}phenyl)pentanamide,-   N-[3-[2-(Cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]butane-1,4-diamine,-   5-[(3aS,4S,6aR)-2-Oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl]-N-(4-{[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl)pentanamide,-   3-[2-(Cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine,-   N,N′-di-tert-butoxycarbonyl-N′-(4-{[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl)guanidine,-   N-(4-{[3-[2-(Cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl)guanidine,-   N-(4-{[3-[2-(Cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl)methanesulfonamide,-   N-{[(4-{[3-[2-(Cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo-[1,5-a]pyridin-7-yl]amino)}butyl)amino]carbonyl}-4-methylbenzenesulfonamide,-   4-[(4-{[3-[2-(Cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl)amino]-4-oxobutanoic    acid,-   Diethyl    4-{[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butylamidophosphate,-   4-{[3-[2-(Cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butan-1-ol,-   Dibenzyl    4-{[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl    phosphate,-   4-{[3-[2-(Cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl    phosphate diammonium salt,-   2-(3-Azidophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-amine,-   3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)-N-[2-oxo-2-(1-pyrrolidinyl)ethyl]pyrazolo[1,5-a]pyridin-7-amine,-   N-(2-{[3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}ethyl)methanesulfonamide,-   N′-[3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]-1,2-ethanediamine,-   N-Cyclopentyl-4-[2-(3-fluorophenyl)-7-(4-morpholinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine,-   N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-7-amine,-   2-(3-Chlorophenyl)-N-cyclopropyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine,-   2-(3-Chlorophenyl)-N-cyclopentyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine,-   2-(3-Chlorophenyl)-3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-cyclopropylpyrazolo[1,5-a]pyridin-7-amine,-   N-Cyclopentyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]-2-(3-fluorophenyl)pyrazolo[1,5-a]pyridin-7-amine,-   4-[2-(3-Chlorophenyl)-7-(4-morpholinyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine,-   2-(3-Chlorophenyl)-3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-(2-methoxyethyl)pyrazolo[1,5-a]pyridin-7-amine,-   3-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-cyclopropyl-2-(3-fluorophenyl)pyrazolo[1,5-a]pyridin-7-amine,-   3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(3-fluorophenyl)-N-(2-methoxyethyl)pyrazolo[1,5-a]pyridin-7-amine,    and-   pharmaceutically acceptable salts, solvates and physiologically    functional derivatives thereof.

Particularly preferred compounds of formula (I) include but are notlimited to:

-   N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)-pyrazolo[1,5-a]pyridin-7-amine,-   2-[4-(Allyloxy)phenyl]-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-    a]pyridin-7-amine,-   N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[4-(cyclopropyl-methoxy)phenyl]pyrazolo[1,5-a]pyridin-7-amine,-   2-(3-Bromophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine,-   N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-phenylpyrazolo-[1,5-a]pyridin-7-amine,-   N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-7-amine;-   N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(3-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine;-   N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[3-(cyclopropylmethoxy)phenyl]pyrazolo[1,5-a]pyridin-7-amine;-   N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(3-fluorophenyl)pyrazolo[1,5-a]pyridin-7-amine;-   2-(3-Chlorophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine;-   N-Cyclopentyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine;-   3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)-N-[2-(4-morpholinyl)ethyl]pyrazolo[1,5-a]pyridin-7-amine;-   3-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-cyclopropyl-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine;-   N-Cyclopentyl-4-[2-(4-methoxyphenyl)-7-(4-morpholinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine;-   3-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-(2-methoxyethyl)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine;-   3-[2-(Cyclopropylamino)-4-pyrimidinyl]-N-(2-methoxyethyl)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine;-   4-[3-[2-(Cyclopentylamino)-4-pyrimidinyl]-7-(cyclopropylamino)pyrazolo[1,5-a]pyridin-2-yl]phenol;-   5-[(3aS,4S,6aR)-2-Oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl]-N-(4-{[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl)pentanamide;-   4-{[3-[2-(Cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)-pyrazolo[1,5-a]pyridin-7-yl]amino}butan-1-ol;-   4-{[3-[2-(Cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxy-phenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl    phosphate diammonium salt;-   N-(2-{[3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxy-phenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}ethyl)methanesulfonamide;-   N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-7-amine;-   2-(3-Chlorophenyl)-N-cyclopentyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine;-   2-(3-Chlorophenyl)-3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-cyclopropylpyrazolo[1,5-a]pyridin-7-amine;-   2-(3-Chlorophenyl)-3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-(2-methoxyethyl)pyrazolo[1,5-a]pyridin-7-amine;    and-   3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(3-fluorophenyl)-N-(2-methoxyethyl)pyrazolo[1,5-a]pyridin-7-amine;    and-   pharmaceutically acceptable salts, solvates and physiologically    functional derivatives thereof.

It will be appreciated by those skilled in the art that the compounds ofthe present invention may also be utilized in the form of apharmaceutically acceptable salt or solvate thereof. Thepharmaceutically acceptable salts of the compounds of formula (I)include conventional salts formed from pharmaceutically acceptableinorganic or organic acids or bases as well as quaternary ammoniumsalts. More specific examples of suitable acid salts includehydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric,fumaric, acetic, propionic, succinic, glycolic, formic, lactic, maleic,tartaric, citric, palmoic, malonic, hydroxymaleic, phenylacetic,glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methanesulfonic,naphthalene-2-sulfonic, benzenesulfonic hydroxynaphthoic, hydroiodic,malic, steroic, tannic and the like. Other acids such as oxalic, whilenot in themselves pharmaceutically acceptable, may be useful in thepreparation of salts useful as intermediates in obtaining the compoundsof the invention and their pharmaceutically acceptable salts. Morespecific examples of suitable basic salts include sodium, lithium,potassium, magnesium, aluminium, calcium, zinc,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, N-methylglucamine and procaine salts.

The term “solvate” as used herein refers to a complex of variablestoichiometry formed by a solute (a compound of formula (I)) and asolvent. Solvents, by way of example, include water, methanol, ethanol,or acetic acid.

The term “physiologically functional derivative” as used herein refersto any pharmaceutically acceptable derivative of a compound of thepresent invention, for example, an ester or an amide of a compound offormula (I), which upon administration to an animal, particularly amammal, such as a human, is capable of providing (directly orindirectly) a compound of the present invention or an active metabolitethereof. See for example, Burger's Medicinal Chemistry And DrugDiscovery, 5th Edition, Vol 1: Principles And Practice.

Processes for preparing pharmaceutically acceptable salts, solvates andphysiologically functional derivatives of the compounds of formula (I)are conventional in the art. See, e.g., Burger's Medicinal Chemistry AndDrug Discovery 5th Edition, Vol 1: Principles And Practice.

As will be apparent to those skilled in the art, in the processesdescribed below for the preparation of compounds of formula (I), certainintermediates, may be in the form of pharmaceutically acceptable salts,solvates or physiologically functional derivatives of the compound.Those terms as applied to any intermediate employed in the process ofpreparing compounds of formula (I) have the same meanings as noted abovewith respect to compounds of formula (I). Processes for preparingpharmaceutically acceptable salts, solvates and physiologicallyfunctional derivatives of such intermediates are known in the art andare analogous to the process for preparing pharmaceutically acceptablesalts, solvates and physiologically functional derivatives of thecompounds of formula (I).

Certain compounds of formula (I) may exist in stereoisomeric forms (e.g.they may contain one or more asymmetric carbon atoms or may exhibitcis-trans isomerism). The individual stereoisomers (enantiomers anddiastereomers) and mixtures of these are included within the scope ofthe present invention. The present invention also covers the individualisomers of the compounds represented by formula (I) as mixtures withisomers thereof in which one or more chiral centers are inverted.Likewise, it is understood that compounds of formula (I) may exist intautomeric forms other than that shown in the formula and these are alsoincluded within the scope of the present invention.

The present invention further provides compounds of formula (I) for usein medical therapy, e.g. in the treatment or prophylaxis, includingsuppression of recurrence of symptoms, of a viral disease in an animal,e.g. a mammal such as a human. The compounds of formula (I) areespecially useful for the treatment or prophylaxis of viral diseasessuch as herpes viral infections. Herpes viral infections include, forexample, herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2),cytomegalovirus (CMV), Epstein Barr virus (EBV), varacella zoster virus(VZV), human herpes virus 6 (HHV-6), human herpes virus 7 (HHV-7), andhuman herpes virus 8 (HHV-8). Thus, the compounds of the invention arealso useful in the treatment or prophylaxis of the symptoms or effectsof herpes virus infections.

The compounds of the invention are useful in the treatment orprophylaxis of conditions or diseases associated with herpes virusinfections, particularly conditions or diseases associated with latentherpes virus infections in an animal, e.g., a mammal such as a human. Byconditions or diseases associated with herpes viral infections is meanta condition or disease, excluding the viral infection per se, whichresults from the presence of the viral infection, such as chronicfatigue syndrome which is associated with EBV infection; and multiplesclerosis which has been associated with herpes viral infections such asEBV and HHV-6. Further examples of such conditions or diseases aredescribed in the background section above.

In addition to those conditions and diseases, the compounds of thepresent invention may also be used for the treatment or prophylaxis ofcardiovascular diseases and conditions associated with herpes virusinfections, in particular atherosclerosis, coronary artery disease andrestenosis and specifically restenosis following angioplasty (RFA).Restenosis is the narrowing of the blood vessels which can occur afterinjury to the vessel wall, for example injury caused by balloonangioplasty or other surgical and/or diagnostic techniques, and ischaracterized by excessive proliferation of smooth muscle cells in thewalls of the blood vessel treated. It is thought that in many patientssuffering from RFA, viral infection, particularly by CMV and/or HHV-6 ofthe patient plays a pivotal role in the proliferation of the smoothmuscle cells in the coronary vessel treated. Restenosis can occurfollowing a number of surgical and/or diagnostic techniques, forexample, transplant surgery, vein grafting, coronary by-pass graftingand, most commonly following angioplasty.

There is evidence from work done both in vitro and in vivo, indicatingthat restenosis is a multifactorial process. Several cytokines andgrowth factors, acting in concert, stimulate the migration andproliferation of vascular smooth muscle cells (SMC) and production ofextracellular matrix material, which accumulate to occlude the bloodvessel. In addition growth suppressors act to inhibit the proliferationof SMC's and production of extracellular matrix material.

In addition, compounds of formula (I) may be useful in the treatment orprophylaxis of hepatitis B or hepatitis C viruses, human papilloma virus(HPV) and HIV.

The present invention provides a method for the treatment or prophylaxisof a viral infection in an animal such as a mammal (e.g., a human),particularly a herpes viral infection, which comprises administering tothe animal a therapeutically effective amount of the compound of formula(I).

As used herein, the term “prophylaxis” refers to the complete preventionof infection, the prevention of occurrence of symptoms in an infectedsubject, the prevention of recurrence of symptoms in an infectedsubject, or a decrease in severity or frequency of symptoms of viralinfection, condition or disease in the subject.

As used herein, the term “treatment” refers to the partial or totalelimination of symptoms or decrease in severity of symptoms of viralinfection, condition or disease in the subject, or the elimination ordecrease of viral presence in the subject.

As used herein, the term “therapeutically effective amount” means anamount of a compound of formula (I) which is sufficient, in the subjectto which it is administered, to treat or prevent the stated disease,condition or infection. For example, a therapeutically effective amountof a compound of formula (I) for the treatment of a herpes virusinfection is an amount sufficient to treat the herpes virus infection inthe subject.

The present invention also provides a method for the treatment orprophylaxis of conditions or diseases associated with herpes viralinfections in an animal such as a mammal (e.g., a human), whichcomprises administering to the animal a therapeutically effective amountof the compound of formula (I). In one embodiment, the present inventionprovides a method for the treatment or prophylaxis of chronic fatiguesyndrome and multiple sclerosis in an animal such as a mammal (e.g., ahuman), which comprises administering to the animal a therapeuticallyeffective amount of a compound of formula (I). The foregoing method isparticularly useful for the treatment or prophylaxis of chronic fatiguesyndrome and multiple sclerosis associated with latent infection with aherpes virus.

In another embodiment, the present invention provides a method for thetreatment or prophylaxis of a cardiovascular condition such asatherosclerosis, coronary artery disease or restenosis (particularlyrestenosis following surgery such as angioplasty), which comprisesadministering to the animal a therapeutically effective antiviral amountof the compound of formula (I).

The present invention further provides a method for the treatment orprophylaxis of hepatitis B or hepatitis C viruses in an animal such as amammal (e.g., a human), which comprises administering to the animal atherapeutically effective amount of the compound of formula (I).

The present invention further provides a method for the treatment orprophylaxis of human papilloma virus in an animal such as a mammal(e.g., a human), which comprises administering to the animal atherapeutically effective amount of the compound of formula (I).

The present invention further provides a method for the treatment orprophylaxis of HIV in an animal such as a mammal (e.g., a human), whichcomprises administering to the animal a therapeutically effective amountof the compound of formula (I).

The present invention also provides the use of the compound of formula(I) in the preparation of a medicament for the treatment or prophylaxisof a viral infection in an animal such as a mammal (e.g., a human),particularly a herpes viral infection; the use of the compound offormula (I) in the preparation of a medicament for the treatment ofconditions or disease associated with a herpes viral infection; and theuse of the compound of formula (I) in the preparation of a medicamentfor the treatment or prophylaxis of hepatitis B or hepatitis C viruses,human papilloma virus and HIV. In particular, the present invention alsoprovides the use of a compound of formula (I) in the preparation of amedicament for the treatment or prophylaxis of chronic fatigue syndromeor multiple sclerosis. In one embodiment, the present invention providesthe use of a compound of formula (I) in the preparation of a medicamentfor the treatment or prophylaxis of cardiovascular disease, such asrestenosis and atherosclerosis.

The compounds of formula (I) are conveniently administered in the formof pharmaceutical compositions. Such compositions may conveniently bepresented for use in conventional manner in admixture with one or morephysiologically acceptable carriers or diluents.

While it is possible that compounds of the present invention may betherapeutically administered as the raw chemical, it is preferable topresent the active ingredient as a pharmaceutical formulation. Thepharmaceutical formulation may comprise a carrier or diluent. Thecarrier(s) or diluent(s) must be “acceptable” in the sense of beingcompatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

Accordingly, the present invention further provides for a pharmaceuticalcomposition or formulation comprising a compound of formula (I). In oneembodiment, the pharmaceutical formulation further comprises one or morepharmaceutically acceptable carriers or dilents and, optionally, othertherapeutic and/or prophylactic ingredients.

The formulations include those suitable for oral, parenteral (includingsubcutaneous e.g. by injection or by depot tablet, intradermal,intrathecal, intramuscular e.g. by depot and intravenous), rectal andtopical (including dermal, buccal and sublingual) administrationalthough the most suitable route may depend upon for example thecondition, age, and disorder of the recipient as well as the viralinfection or disease being treated. The formulations may conveniently bepresented in unit dosage form and may be prepared by any of the methodswell known in the art of pharmacy. All methods include the step ofbringing into association the compound(s) (“active ingredient”) with thecarrier which constitutes one or more accessory ingredients. In generalthe formulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both and then, if necessary, shaping the product intothe desired formulation. Formulations suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tablets(e.g. chewable tablets in particular for paediatric administration) eachcontaining a predetermined amount of the active ingredient; as a powderor granules; as a solution or a suspension in an aqueous liquid or anon-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also bepresented as a bolus, electuary or paste. A tablet may be made bycompression or moulding, optionally with one or more accessoryingredients. Compressed tablets may be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such as apowder or granules, optionally mixed with other conventional excipientssuch as binding agents, (for example, syrup, acacia, gelatin, sorbitol,tragacanth, mucilage of starch or polyvinylpyrrolidone), fillers (forexample, lactose, sugar, microcrystalline cellulose, maize-starch,calcium phosphate or sorbitol), lubricants (for example, magnesiumstearate, stearic acid, talc, polyethylene glycol or silica),disintegrants (for example, potato starch or sodium starch glycollate)or wetting agents, such as sodium lauryl sulfate. Moulded tablets may bemade by moulding in a suitable machine a mixture of the powderedcompound moistened with an inert liquid diluent. The tablets mayoptionally be coated or scored and may be formulated so as to provideslow or controlled release of the active ingredient therein. The tabletsmay be coated according to methods well-known in the art.

Alternatively, the compounds of the present invention may beincorporated into oral liquid preparations such as aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, for example.Moreover, formulations containing these compounds may be presented as adry product for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may contain conventional additives such assuspending agents such as sorbitol syrup, methyl cellulose,glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats;emulsifying agents such as lecithin, sorbitan mono-oleate or acacia;non-aqueous vehicles (which may include edible oils) such as almond oil,fractionated coconut oil, oily esters, propylene glycol or ethylalcohol; and preservatives such as methyl or propyl p-hydroxybenzoatesor sorbic acid. Such preparations may also be formulated assuppositories, e.g., containing conventional suppository bases such ascocoa butter or other glycerides.

Formulations for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents.

The formulations may be presented in unit-dose or multi-dose containers,for example sealed ampoules and vials, and may be stored in afreeze-dried (lyophilised) condition requiring only the addition of asterile liquid carrier, for example, water-for-injection, immediatelyprior to use. Extemporaneous injection solutions and suspensions may beprepared from sterile powders, granules and tablets of the kindpreviously described.

Formulations for rectal administration may be presented as a suppositorywith the usual carriers such as cocoa butter, hard fat or polyethyleneglycol.

Formulations for topical administration in the mouth, for examplebuccally or sublingually, include lozenges comprising the activeingredient in a flavoured base such as sucrose and acacia or tragacanth,and pastilles comprising the active ingredient in a base such as gelatinand glycerin or sucrose and acacia.

The compounds may also be formulated as depot preparations. Such longacting formulations may be administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection. Thus,for example, the compounds may be formulated with suitable polymeric orhydrophobic materials (for example as an emulsion in an acceptable oil)or ion exchange resins, or as sparingly soluble derivatives, forexample, as a sparingly soluble salt.

In addition to the ingredients particularly mentioned above, theformulations may include other agents conventional in the art havingregard to the type of formulation in question, for example thosesuitable for oral administration may include flavouring agents.

It will be appreciated that the amount of a compound of the inventionrequired for use in treatment will vary with the nature of the conditionbeing treated and the age and the condition of the patient and will beultimately at the discretion of the attendant physician or veterinarian.In general, however, doses employed for adult human treatment willtypically be in the range of 0.02–5000 mg per day, preferably 100–1500mg per day. The desired dose may conveniently be presented in a singledose or as divided doses administered at appropriate intervals, forexample as two, three, four or more sub-doses per day. The formulationsaccording to the invention may contain between 0.1–99% of the activeingredient, conveniently from 30–95% for tablets and capsules and 3–50%for liquid preparations.

The compound of formula (I) for use in the instant invention may be usedin combination with other therapeutic agents for example, non-nucleotidereverse transcriptase inhibitors, nucleoside reverse transcriptaseinhibitors, protease inhibitors and/or other antiviral agents. Theinvention thus provides in a further aspect the use of a combinationcomprising a compound of formula (I) with a further therapeutic agent inthe treatment of viral infections. Particular antiviral agents which maybe combined with the compounds of the present invention includeaciclovir, valaciclovir, famcyclovir, docosanol, gancyclovir, miribavir,amprenavir, lamivudine, zidovudine, and abacavir. Preferred antiviralagents for combining with the compounds of the present invention includeaciclovir and valaciclovir. Thus the present invention provides in afurther aspect, a combination comprising a compound of formula (I) andan antiviral agent selected from the group consisting of aciclovir andvalaciclovir; the use of such combination in the treatment of viralinfections and the preparation of a medicament for the treatment ofviral infections, and a method of treating viral infections comprisingadministering a compound of formula (I) and an antiviral agent selectedfrom the group consisting of aciclovir and valaciclovir.

When the compounds of formula (I) are used in combination with othertherapeutic agents, the compounds may be administered eithersequentially or simultaneously by any convenient route.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical formulation and thus pharmaceuticalformulations comprising a combination as defined above optionallytogether with a pharmaceutically acceptable carrier or diluent comprisea further aspect of the invention. The individual components of suchcombinations may be administered either sequentially or simultaneouslyin separate or combined pharmaceutical formulations.

When combined in the same formulation it will be appreciated that thetwo compounds must be stable and compatible with each other and theother components of the formulation and may be formulated foradministration. When formulated separately they may be provided in anyconvenient formulation, in such a manner as are known for such compoundsin the art.

When a compound of formula (I) is used in combination with a secondtherapeutic agent active against the viral infection, the dose of eachcompound may differ from that when the compound is used alone.Appropriate doses will be readily appreciated by those skilled in theart.

Compounds of formula (I) wherein Y is N and R² is selected from thegroup consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, —NR⁷R⁸,—OR⁷, Ay, —OAy, —S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, Het,—NHHet, —NHR¹⁰Het, —OHet, and —OR¹⁰Het, and R³ and R⁴ are H, may beconveniently prepared by the general process outlined in Scheme 1 below.

wherein:

-   R¹ is selected from the group consisting of halo, —NR⁷R⁸, Ay,    —NR⁷Ay, Het, —NHR¹⁰Het, —NHHet and —NHR¹⁰Ay;    -   each R⁷ and R⁸ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        alkenyl, cycloalkenyl, —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹,        —R¹⁰C(O)R⁹, —C(O)R⁹, —C(O)R¹⁰Ay, —C(O)R¹⁰Het, —CO₂R⁹, —R¹⁰CO₂R⁹,        —C(O)NR⁹R¹¹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(O)Ay, —R¹⁰C(O)Het,        —C(S)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹,        —R¹⁰NHC(O)R¹⁰Het, —R¹⁰NHC(O)R¹⁰CO₂R⁹, —R¹⁰NHC(NCO₂R⁹)NHCO₂R⁹,        —R¹⁰NHC(O)NHSO₂R⁹, —R¹⁰NHC(O)NHSO₂Ay, —R¹⁰NHC(O)NHSO₂Het,        —R¹⁰C(NH)NR⁹R¹¹, —C(NH)NR⁹R¹¹, —SO₂NR⁹R¹¹, —R¹⁰SO₂NR⁹R¹¹,        —R¹⁰NHSO₂R⁹, —SO₂R¹⁰, —R¹⁰SO₂R¹⁰, —R¹⁰NHCOR⁹, —R¹⁰SO₂NHCOR⁹,        —R¹⁰NHP(O)(OR⁹)₂, —R¹⁰OP(O)(OR⁹)₂ and —R¹⁰OP(O)(OR¹⁰Ay)₂;    -   each R⁹ and R¹¹ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        —R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) where w is 1–10, and        —R¹⁰NR¹⁰R¹⁰;    -   each R¹⁰ is the same or different and is independently selected        from the group consisting of alkyl, cycloalkyl, alkenyl,        cycloalkenyl and alkynyl;    -   Ay is aryl;    -   Het is a 5- or 6-membered heterocyclic or heteroaryl group;-   R² is selected from the group consisting of alkyl, cycloalkyl,    alkenyl, cycloalkenyl, Ay, —NR⁷R⁸, —OR⁷, —OAy, —S(O)_(n)R⁹,    —S(O)_(n)Ay, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, Het, —NHHet, —NHR¹⁰Het, —OHet and    —OR¹⁰Het;-   n is 0, 1 or 2;-   Y is N;-   R³ and R⁴ are both H;-   q is 0, 1, 2, 3, 4 or 5;-   each R⁵ is the same or different and is independently selected from    the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, —R¹⁰cycloalkyl, Ay, —NHR¹⁰Ay, Het, —NHHet, —NHR¹⁰Het,    —OR⁷, —OAy, —OHet, —R¹⁰OR⁹, —NR⁷R⁸, —NR⁷Ay, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay,    —R¹⁰C(O)R⁹, —C(O)R⁹, —CO₂R⁹, —R¹⁰CO₂R⁹, —C(O)NR⁷R⁸, —C(O)Ay,    —C(O)NR⁷Ay, —C(O)Het, —C(O)NHR¹⁰Het —R¹⁰C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹,    —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay,    —R¹⁰C(NH)NR⁹R¹¹, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰SO₂NHCOR⁹,    —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂R⁹, —S(O)_(n)R⁹, cyano, nitro and azido; or-    two adjacent R⁵ groups together with the atoms to which they are    bonded form a C₅₋₆ cycloalkyl or aryl;-   wherein when q is 1 and R⁵ is in the para position, R⁵ is not halo;    and-   Rg is Ay or Het as defined above;-   M³ is B(OH)₂, B(ORa)₂, B(Ra)₂, Sn(Ra)₃, Zn-halide, Zn—Ra or    Mg-halide;-   Ra is alkyl or cycloalkyl; and-   halide is halo.

Generally, the process for preparing the compounds of formula (I)wherein Y is N and R² is selected from the group consisting of alkyl,cycloalkyl, alkenyl, cycloalkenyl, —NR⁷R⁸, —OR⁷, Ay, —OAy, —S(O)_(n)R⁹,—S(O)_(n)Ay, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, Het, —NHHet, —NHR¹⁰Het, —OHet, and—OR¹⁰Het, and R³ and R⁴ are H, (all formulas and all other variableshaving been defined above in connection with Scheme 1) comprises thesteps of:

-   (a) reacting 2-chloro-6-picoline with a benzoylating agent of    formula (II) to prepare a compound of formula (III);-   (b) reacting the compound of formula (III) with a hydroxylamine    source to prepare a compound of formula (IV);-   (c) reacting the compound of formula (IV) with an acylating or    sulfonylating agent to prepare a compound of formula (V);-   (d) rearranging the compound of formula (V) to prepare a compound of    formula (VI);-   (e) acylating the compound of formula (VI) to prepare a compound of    formula (VII);-   (f) either:    -   (1) replacing the C-7 halogen of the compound of formula (VII)        with an amine; or    -   (2) coupling the compound of formula (VII) with a metal compound        of the formula Rg-M³        to prepare a compound of formula (VIII);-   (g) reacting the compound of formula (VIII) with a dimethylformamide    dialkyl acetal of formula (CH₃)₂NCH(ORa)₂ to prepare a compound of    formula (IX); and-   (h) reacting the compound of formula (IX) with a compound of    formula (X) to prepare the compounds of formula (I).

More specifically, compounds of formula (I) wherein Y is N and R² isselected from the group consisting of alkyl, cycloalkyl, alkenyl,cycloalkenyl, —NR⁷R⁸, —OR⁷, Ay, —OAy, —S(O)_(n)R⁹, —S(O)_(n)Ay,—R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, Het, —NHHet, —NHR¹⁰Het, —OHet, and —OR¹⁰Het, andR³ and R⁴ are H can be prepared by reacting a compound of formula (IX)with a compound of formula (X).

wherein all variables are as defined above in connection with Scheme 1.

This method can be readily carried out by mixing a compound of formula(IX) with a compound of formula (X) in a suitable solvent, optionally inthe presence of a base (preferably when the amidine is in a salt form),and heating the reaction to 50–150° C. Typical solvents include loweralcohols such as methanol, ethanol, isopropanol, dimethylformamide, orthe like. The base is typically a sodium alkoxide, potassium carbonate,or an amine base such as triethylamine. In one embodiment, the solventis dimethylformamide and the base is potassium carbonate, or an aminebase such as triethylamine.

Compounds of the formula (IX) may be conveniently prepared by reacting acompound of formula (VIII) with a dimethylformamide dialkyl acetal.

wherein all variables are as defined above in connection with Scheme 1.

Typical dimethylformamide dialkylacetal compounds for use in this methodinclude but are not limited to dimethylformamide dimethylacetal anddimethylformamide di-tert-butylacetal. The reaction is carried out bymixing a compound of formula (VIII) with the dimethylformamide dialkylacetal, optionally with heating.

Compounds of the formula (VIII) may be prepared by two methods.According to one method, compounds of formula (VIII) are prepared fromcompounds of formula (VII) by replacement of the C-7 halogen (chloro isdepicted in formula (VII) but other halogens are similarly useful) withan amine nucleophile.

wherein all variables are as defined above in connection with Scheme 1.

Typically the replacement is carried out by mixing the compound offormula (VII) with an amine nucleophile of formula R^(1a) where R^(1a)is selected from the group consisting of —NR⁷R⁸, —NR⁷Ay, Het, —NHR¹⁰Het,NHHet, and —NHR¹⁰Ay; and optionally heating the reaction.

The reaction can also be carried out via an adaptation of proceduresfound in the literature (Wolfe, J. P.; Buchwald, S. L. J. Org. Chem.2000, 65, 1144) wherein a compound of formula (VII) is treated with anamine, a palladium (0) or nickel (0) source and a base in a suitablesolvent. Suitable sources of palladium (0) include but are not limitedto palladium(II) acetate and tris(dibenzylideneacetone) dipalladium (0).Typical bases for use in the reaction include, for example sodiumtert-butoxide and cesium carbonate. Toluene is an example of a suitablesolvent.

According to the second method, compounds of formula (VIII) are preparedfrom compounds of formula (VII) by coupling with metal compounds of theformula Rg-M³ wherein Rg is Ay or Het as defined above and M³ is B(OH)₂,B(ORa)₂, B(Ra)₂, Sn(Ra)₃, Zn-halide, Zn—Ra or Mg-halide, wherein Ra isalkyl or cycloalkyl and halide is halo. This general method can beconveniently performed in an inert solvent, in the presence of apalladium (0) catalyst, optionally with heating. Preferably the reactionis performed by reacting equimolar amounts of a compound of formula(VII) with the metal compound of formula Rg-M³ or optionally adding anexcess of the metal compound. The palladium catalyst is preferrablypresent in 1–10 mol % compared to the compound of formula (VII).Palladium catalysts that may be used may include, but are not limitedto, tetrakistriphenylphosphine palladium (0)dichlorobis(triphenylphosphine)palladium(II), andbis(diphenylphosphinoferrocene)-palladium (II) dichloride. Inertsolvents for use in the reaction include but are not limited to,N,N-dimethylformamide, toluene, tetrahydrofuran, dioxane, and1-methyl-2-pyrrolidinone.

When the metal compound of formula Rg-M³ is an arylboronic acid or esteror an arylborinate, the reaction is more conveniently carried out byadding a base in a proportion equivalent to, or greater than, that ofthe metal compound.

Metal compounds of the formula Rg-M³ can be purchased from commercialsources or prepared either as discreet isolated compounds or generatedin situ by using methods known to one skilled in the art. (Suzuki, A. J.Organomet. Chem. 1999, 576, 147; Stille, J. Angew. Chem. Int. Ed. Engl.1986, 25, 508; Snieckus, V. J. Org. Chem. 1995, 60, 292.)

Compounds of formula (VII) may be conveniently prepared from compoundsof formula (VI) using an acylation procedure.

wherein all variables are as defined above in connection with Scheme 1.

Typically the acylation is carried out by treating the compounds offormula (VI) with an acylating agent, optionally in the presence of anacid or Lewis acid catalyst in an inert solvent with optional heating.Typical acylating agents will be readily determined by those skilled inthe art. One preferred acylating agent is acetic anhydride. Lewis acidcatalysts are also known to those skilled in the art. One preferredLewis acid catalyst for use in this reaction is boron trifluoridediethyl etherate. A suitable solvent is toluene.

Compounds of formula (VI) are conveniently prepared by rearranging anazirine compound of formula (V).

wherein all variables are as defined above in connection with Scheme 1.

The rearrangement of the azirines of formula (V) can be accomplished byheating a solution of the azirine of formula (V) in a suitable solventat a temperature of about 160–200° C. Suitable inert solvents include,but are not limited to, 1-methyl-2-pyrrolidinone, and1,2,4-trichlorobenzene. A more preferred method for rearrangement of theazirine of formula (V) to compounds of formula (VI) involves reactingthe compound of formula (V) with ferrous chloride (FeCl₂) or ferricchloride (FeCl₃). This reaction is typically done in an inert solventwith heating. A preferred solvent for this reaction is1,2-dimethoxyethane and the like.

Typically the azirines of formula (V) are prepared from oxime compoundsof formula (IV) by treatment with acylating or sulfonylating agents inthe presence of a base.

wherein all variables are as defined above in connection with Scheme 1.

Typical acylating or sulfonylating agents include but are not limitedto, acetic anhydride, trifluoroacetic anhydride, methanesulfonylchloride, toluenesulfonyl chloride and the like. Typical bases include,but are not limited to, triethylamine, diisopropylethylamine, pyridine,or the like. The reaction may be carried out in an inert solvent such asfor example, chloroform, dichloromethane, toluene or the like.

The oxime compounds of formula (IV) are readily prepared by treatingketone compounds of formula (III) with a hydroxylamine source, in asuitable solvent, and optionally with a base.

wherein all variables are as defined above in connection with Scheme 1.

Preferrably the hydroxylamine is hydroxylamine hydrochloride and thebase is an aqueous solution of sodium hydroxide. Suitable solventsinclude lower alcohols such as methanol, ethanol, or isopropanol.

The ketone compounds of formula (III) can be prepared by treatment of2-chloro-6-picoline with a benzoylating agent of formula (II) in thepresence of a base.

wherein all variables are as defined above in connection with Scheme 1.

Preferred benzoylating agents of formula (II) include, but are notlimited to, benzoyl esters. An example of a suitable base is lithiumbis(trimethylsilyl)amide in an inert solvent such as tetrahydrofuran.Ketones such as those of formula (III) can be readily prepared usingprocedures known to one skilled in the art and/or described in theliterature (Cassity, R. P.; Taylor, L. T.; Wolfe, J. F. J.Org. Chem.1978, 2286).

In addition to the foregoing process for preparing certain compounds offormula (I), the present invention also provides certain intermediatecompounds for use in the preparation of such compounds of formula (I)according to the foregoing process.

Thus, as one aspect, the present invention provides compounds of formula(II)

wherein all variables are as defined above in connection with Scheme 1and Et is ethyl.

As another aspect, the present invention provides compounds of formula(III)

wherein all variables are as defined above in connection with Scheme 1.

As another aspect, the present invention provides compounds of formula(IV)

wherein all variables are as defined above in connection with Scheme 1.

As another aspect, the present invention provides compounds of formula(V)

wherein all variables are as defined above in connection with Scheme 1.

As another aspect, the present invention provides compounds of formula(VI)

wherein all variables are as defined above in connection with Scheme 1.

As another aspect, the present invention provides compounds of formula(VII)

wherein all variables are as defined above in connection with Scheme 1.

As another aspect, the present invention provides compounds of formula(VIII)

wherein all variables are as defined above in connection with Scheme 1.

As another aspect, the present invention provides compounds of formula(IX)

wherein all variables are as defined above in connection with Scheme 1.

In a further embodiment of the present invention, compounds of formula(I) wherein Y is N; R² is selected from the group consisting of H,alkyl, cycloalkyl, alkenyl, cycloalkenyl, —NR⁷R⁸, —OR⁷, Ay, —OAy,—S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, Het, —NHHet, —NHR¹⁰Het,—OHet, and —OR¹⁰Het; R³ is selected from the group consisting of H,alkyl, cycloalkyl, alkenyl, —R¹⁰OR⁷, —R¹⁰OAy, —NR⁷R⁸ where R⁷ and R⁸ arenot H, Ay, —NR⁷Ay where R⁷ is not H, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —C(O)R⁷,—C(O)Ay, —CO₂R⁷, —CO₂Ay, —SO₂NHR⁹ and Het; and R⁴ is H, may beconveniently prepared by a general process outlined in Scheme 2 below.

wherein:

-   R¹ is selected from the group consisting of halo, —NR⁷R⁸, Ay,    —NR⁷Ay, Het, —NHR¹⁰Het, —NHHet and —NHR¹⁰Ay;    -   each R⁷ and R⁸ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        alkenyl, cycloalkenyl, —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹,        —R¹⁰C(O)R⁹, —C(O)R⁹, —C(O)R¹⁰Ay, —C(O)R¹⁰Het, —CO₂R⁹, —R¹⁰OC₂R⁹,        —C(O)NR⁹R¹¹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(O)Ay, —R¹⁰C(O)Het,        —C(S)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹,        —R¹⁰NHC(O)R¹⁰Het, —R¹⁰NHC(O)R¹⁰CO₂R⁹, —R¹⁰NHC(NCO₂R⁹)NHCO₂R⁹,        —R¹⁰NHC(O)NHSO₂R⁹, —R¹⁰NHC(O)NHSO₂Ay, —R¹⁰NHC(O)NHSO₂Het,        —R¹⁰C(NH)NR⁹R¹¹, —C(NH)NR⁹R¹¹, —SO₂NR⁹R¹¹, —R¹⁰SO₂NR⁹R¹¹,        —R¹⁰NHSO₂R⁹, —SO₂R¹⁰, —R¹⁰SO₂R¹⁰, —R¹⁰NHCOR⁹, —R¹⁰SO₂NHCOR⁹,        —R¹⁰NHP(O)(OR⁹)₂, —R¹⁰OP(O)(OR⁹)₂ and —R¹⁰OP(O)(OR¹⁰Ay)₂;    -   each R⁹ and R¹¹ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        —R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) where w is 1–10, and        —R¹⁰NR¹⁰R¹⁰;    -   each R¹⁰ is the same or different and is independently selected        from the group consisting of alkyl, cycloalkyl, alkenyl,        cycloalkenyl and alkynyl;    -   Ay is aryl;    -   Het is a 5- or 6-membered heterocyclic or heteroaryl group;-   R² is selected from the group consisting of alkyl, cycloalkyl,    alkenyl, cycloalkenyl, Ay, —NR⁷R⁸, —OR⁷, —OAy, —S(O)_(n)R⁹,    —S(O)_(n)Ay, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, Het, —NHHet, —NHR¹⁰Het, —OHet and    —OR¹⁰Het;-   n is 0, 1 or 2;-   Y is N;-   R³ is selected from the group consisting of H, alkyl, cycloalkyl,    alkenyl, Ay, —R¹⁰OR⁷, —R¹⁰OAy, —NR⁷R⁸ where R⁷ and R⁸ are not H,    —NR⁷Ay where R⁷ is not H, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —C(O)R⁷, —C(O)Ay,    —CO₂R⁷, —CO₂Ay, —SO₂NHR⁹ and Het;-   R⁴ is H;-   q is 0, 1, 2, 3, 4 or 5;-   each R⁵ is the same or different and is independently selected from    the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, —R¹⁰cycloalkyl, Ay, —NHR¹⁰Ay, Het, —NHHet, —NHR¹⁰Het,    —OR⁷, —OAy, —OHet, —R¹⁰OR⁹, —NR⁷R⁸, —NR⁷Ay, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay,    —R¹⁰C(O)R⁹, —C(O)R⁹, —CO₂R⁹, —R¹⁰CO₂R⁹, —C(O)NR⁷R⁸, —C(O)Ay,    —C(O)NR⁷Ay, —C(O)Het, —C(O)NHR¹⁰Het —R¹⁰C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹,    —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay,    —R¹⁰C(NH)NR⁹R¹¹, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰SO₂NHCOR⁹,    —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂R⁹, —S(O)_(n)R⁹, cyano, nitro and azido; or-    two adjacent R⁵ groups together with the atoms to which they are    bonded form a C₅₋₆ cycloalkyl or aryl;-   wherein when q is 1 and R⁵ is in the para position, R⁵ is not halo;    and-   M¹ is Li, Mg-halide or cerium-halide, wherein halide is halo.

Generally, the process for preparing compounds of formula (I) wherein Yis N; R² is selected from the group consisting of alkyl, cycloalkyl,alkenyl, cycloalkenyl, —NR⁷R⁸, —OR⁷, Ay, —OAy, —S(O)_(n)R⁹, —S(O)_(n)Ay,—R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, Het, —NHHet, —NHR¹⁰Het, —OHet, and —OR¹⁰Het; R³ isselected from the group consisting of H, alkyl, cycloalkyl, alkenyl,—R¹⁰OR⁷, —R¹⁰OAy, —NR⁷R⁸ where R⁷ and R⁸ are not H, Ay, —NR⁷Ay where R⁷is not H, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —C(O)R⁷, —C(O)Ay, —CO₂R⁷, —CO₂Ay,—SO₂NHR⁹ and Het; and R⁴ is H (all other variables having been definedabove in connection with Scheme 2), comprises the following steps:

-   (a) reacting a compound of formula (IV-A) with an acylating or    sulfonylating agent to prepare a compound of formula (V-A);-   (b) rearranging the compound of formula (V-A) to prepare a compound    of formula (XII);-   (c) formylating the compound of formula (XII) to prepare a compound    of formula (XIII);-   (d) reacting the compound of formula (XIII) with a compound of    formula (XIV) to prepare a compound of formula (XV);-   (e) oxidizing the compound of formula (XV) to prepare a compound of    formula (XVI); and-   (f) reacting the compound of formula (XVI) with a compound of    formula (X) to prepare the compounds of formula (I).

More specifically, compounds of formula (I) wherein Y is N; R² isselected from the group consisting of alkyl, cycloalkyl, alkenyl,cycloalkenyl, —NR⁷R⁸, —OR⁷, Ay, —OAy, —S(O)_(n)R⁹, —S(O)_(n)Ay,—R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, Het, —NHHet, —NHR¹⁰Het, —OHet, and —OR¹⁰Het; R³ isselected from the group consisting of H, alkyl, cycloalkyl, alkenyl,—R¹⁰OR⁷, —R¹⁰OAy, —NR⁷R⁸ where R⁷ and R⁸ are not H, Ay, —NR⁷Ay where R⁷is not H, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —C(O)R⁷, —C(O)Ay, —CO₂R⁷, —CO₂Ay,—SO₂NHR⁹ and Het; and R⁴ is H, may be prepared by reacting a compound offormula (XVI) with a compound of formula (X).

wherein all variables are as defined above in connection with Scheme 2.

This method can be readily carried out by mixing a compound of formula(XVI) with a compound of formula (X) in a suitable solvent, optionallyin the presence of a base. The reaction may be heated to 50–150° C. orperformed at ambient temperature. Typical solvents include but are notlimited to lower alcohols such as methanol, ethanol, isopropanol and thelike. Typical bases include for example, sodium alkoxide, potassiumcarbonate, or an amine base such as triethylamine. In anotherembodiment, the solvent is N,N-dimethylformamide and the base ispotassium carbonate, or an amine base such as triethylamine.

Compounds of formula (XVI) may be conveniently prepared by oxidation ofa compound of formula (XV).

wherein all variables are as defined above in connection with Scheme 2.

Preferred oxidizing agents include but are not limited to, manganesedioxide, and the like, in an inert solvent. Suitable inert solventsinclude but are not limited to, dichloromethane, chloroform,N,N-dimethylformamide, ether, and the like.

Compounds of formula (XV) may be conveniently prepared by reacting acompound of formula (XIII) with a compound of formula (XIV).

wherein all variables are as defined above in connection with Scheme 2.

Preferred metals (M¹) in the compounds of formula (XIV) include but arenot limited to, lithium, magnesium(II) halides, cerium(III) halides, andthe like. Compounds of formula (XIV) may be purchased from commercialsources or prepared by methods known to one skilled in the art.

Compounds of formula (XIII) may be conveniently prepared from compoundsof formula (XII) by a formylation procedure.

wherein all variables are as defined above in connection with Scheme 2.

Typically the formylation is carried out via the Vilsmeier-Haackreaction. The Vilsmeier-Haack reagents can be purchased from commercialsources or prepared in situ. Preferable conditions include, but are notlimited to treating compounds of formula (XII) with a premixed solutionof phosphorous oxychloride in N,N-dimethylformamide optionally withheating the reaction to 50–150° C.

The compounds of formula (XII) are prepared by a process analogous tothe process employed for the preparation of compounds of formula (VI) inScheme 1 above.

In addition to the foregoing process for preparing certain compounds offormula (I), the present invention also provides certain intermediatecompounds for use in the preparation of such compounds of formula (I)according to the foregoing process. Thus, as one aspect, the presentinvention provides compounds of formula (III-A)

wherein all variables are as defined above in connection with Scheme 2.

As another aspect, the present invention provides compounds of formula(IV-A)

wherein all variables are as defined above in connection with Scheme 2.

As another aspect, the present invention provides compounds of formula(V-A)

wherein all variables are as defined above in connection with Scheme 2.

As another aspect, the present invention provides compounds of formula(XII)

wherein all variables are as defined above in connection with Scheme 2.

In another aspect, the present invention provides compounds of formula(XIII)

wherein all variables are as defined above in connection with Scheme 2.

In another aspect, the present invention provides compounds of formula(XV)

wherein all variables are as defined above in connection with Scheme 2.

In another aspect, the present invention provides compounds of formula(XVI)

wherein all variables are as defined above in connection with Scheme 2.

Compounds of formula (I) wherein Y is N and R² is selected from thegroup consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, —NR⁷R⁸,—OR⁷, Ay, —OAy, —S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, Het,—NHHet, —NHR¹⁰Het, —OHet, and —OR¹⁰Het, may be conveniently prepared bythe process outlined in Scheme 3 below.

wherein:

-   R¹ is selected from the group consisting of halo, —NR⁷R⁸, Ay,    —NR⁷Ay, Het, —NHR¹⁰Het, —NHHet and —NHR¹⁰Ay;    -   each R⁷ and R⁸ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        alkenyl, cycloalkenyl, —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹,        —R¹⁰C(O)R⁹, —C(O)R⁹, —C(O)R¹⁰Ay, —C(O)R¹⁰Het, —CO₂R⁹, —R¹⁰CO₂R⁹,        —C(O)NR⁹R¹¹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(O)Ay, —R¹⁰C(O)Het,        —C(S)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹,        —R¹⁰NHC(O)R¹⁰Het, —R¹⁰NHC(O)R¹⁰CO₂R⁹, —R¹⁰NHC(NCO₂R⁹)NHCO₂R⁹,        —R¹⁰NHC(O)NHSO₂R⁹, —R¹⁰NHC(O)NHSO₂Ay, —R¹⁰NHC(O)NHSO₂Het,        —R¹⁰C(NH)NR⁹R¹¹, —C(NH)NR⁹R¹¹, —SO₂NR⁹R¹¹, —R¹⁰SO₂NR⁹R¹¹,        —R¹⁰NHSO₂R⁹, —SO₂R¹⁰, —R¹⁰SO₂R¹⁰, —R¹⁰NHCOR⁹, —R¹⁰SO₂NHCOR⁹,        —R¹⁰NHP(O)(OR⁹)₂, —R¹⁰OP(O)(OR⁹)₂ and —R¹⁰OP(O)(OR¹⁰Ay)₂;    -   each R⁹ and R¹¹ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl, —R¹⁰        cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) wherein w is 1–10, and        —R¹⁰NR¹⁰R¹⁰;    -   each R¹⁰ is the same or different and is independently selected        from the group consisting of alkyl, cycloalkyl, alkenyl,        cycloalkenyl and alkynyl;    -   Ay is aryl;    -   Het is a 5- or 6-membered heterocyclic or heteroaryl group;-   R² is selected from the group consisting of alkyl, cycloalkyl,    alkenyl, cycloalkenyl, Ay, —NR⁷R⁸, —OR⁷, —OAy, —S(O)_(n)R⁹,    —S(O)_(n)Ay, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, Het, —NHHet, —NHR¹⁰Het, —OHet and    —OR¹⁰ Het;-   n is 0, 1 or 2;-   Y is N;-   R³ and R⁴ are the same or different and are each independently    selected from the group consisting of H, halo, alkyl, cycloalkyl,    alkenyl, Ay, —OR⁷, —OAy, —R¹⁰OR⁷, —R¹⁰Ay, —NR⁷R⁸, —NR⁷Ay, —R¹⁰NR⁷R⁸,    —R¹⁰NR⁷Ay, —C(O)R⁷, —C(O)Ay, —CO₂R⁷, —CO₂Ay, —SO₂NHR⁹, Het, —NHHet    and —NHR¹⁰Het;-   q is 0, 1, 2, 3, 4 or 5;-   each R⁵ is the same or different and is independently selected from    the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, —R¹⁰cycloalkyl, Ay, —NHR¹⁰Ay, Het, —NHHet, —NHR¹⁰Het,    —OR⁷, —OAy, —OHet, —R¹⁰OR⁹, —NR⁷R⁸, —NR⁷Ay, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay,    —R¹⁰C(O)R⁹, —C(O)R⁹, —CO₂R⁹, —R¹⁰CO₂R⁹, —C(O)NR⁷R⁸, —C(O)Ay,    —C(O)NR⁷Ay, —C(O)Het, —C(O)NHR¹⁰Het —R¹⁰C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹,    —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay,    —R¹⁰C(NH)NR⁹R¹¹, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰SO₂NHCOR⁹,    —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂R⁹, —S(O)_(n)R⁹, cyano, nitro and azido; or-    two adjacent R⁵ groups together with the atoms to which they are    bonded form a C₅₋₆ cycloalkyl or aryl;-   wherein when q is 1 and R⁵ is in the para position, R⁵ is not halo;    and-   M¹ is Li, Mg-halide or cerium-halide, wherein halide is halo.

Generally, the process for preparing compounds of formula (I) wherein Yis N and R² is selected from the group consisting of alkyl, cycloalkyl,alkenyl, cycloalkenyl, —NR⁷R⁸, —OR⁷, Ay, —OAy, —S(O)_(n)R⁹, —S(O)_(n)Ay,—R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, Het, —NHHet, —NHR¹⁰Het, —OHet, and —OR¹⁰Het, (allformulas and all other variables having been defined above in connectionwith Scheme 3), comprises the following steps:

-   (a) reacting a compound of formula (XIII) with a compound of    formula (XVIII) to prepare a compound of formula (XIX);-   (b) oxidizing the compound of formula (XIX) to prepare a compound of    formula (XX); and-   (c) reacting a compound of formula (XX) with a compound of    formula (X) followed by oxidative aromatization to prepare the    compounds of formula (I).

More specifically, compounds of formula (I) wherein Y is N and R² isselected from the group consisting of alkyl, cycloalkyl, alkenyl,cycloalkenyl, —NR⁷R⁸, —OR⁷, Ay, —OAy, —S(O)_(n)R⁹, —S(O)_(n)Ay,—R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, Het, —NHHet, —NHR¹⁰Het, —OHet, and —OR¹⁰Het can beprepared by reacting a compound of formula (XX) with a compound offormula (X) followed by oxidative aromatization.

wherein all variables are as defined above in connection with Scheme 3.

The condensation is conveniently carried out by treating the compound offormula (XX) with a compound of formula (X) in an inert solvent,optionally in the presence of a base. The reaction may be heated to50–150° C. or performed at ambient temperature. Suitable inert solventsinclude lower alcohols such as, for example, methanol, ethanol,isopropanol and the like. The base is typically sodium alkoxide,potassium carbonate, or an amine base such as triethylamine. In anotherembodiment, the solvent is N,N-dimethylformamide and the base ispotassium carbonate, or an amine base such as triethylamine. Thereaction produces a dihydropyrimidine intermediate.

Preferrably in the same reaction vessel, the dihydropyrimidineintermediate may be oxidized to a compound of formula (I) by theaddition of an oxidizing agent. The reaction may be heated to 50–150° C.or performed at ambient temperature. Preferrably, the oxidizing agent isoxygen (O₂), palladium on carbon,2,3-dichloro-5,6-dicyano-1,4-benzoquinone, or the like.

Compounds of formula (XX) may be conveniently prepared by oxidation ofcompounds of formula (XIX).

wherein all variables are as defined above in connection with Scheme 3.

Preferred oxidizing agents for the oxidation of compounds of formula(XIX) include but are not limited to manganese dioxide, and the like.The oxidation is typically carried out in an inert solvent such as forexample, dichloromethane, chloroform, N,N-dimethylformamide, ether, andthe like.

Compounds of formula (XIX) may be conveniently prepared by reacting acompound of formula (XIII) with a compound of formula (XVIII).

wherein M¹ is a metal such as for example, lithium, magnesium(II)halides, cerium(III) halides, and the like and all other variables areas defined above in connection with Scheme 3. Compounds of formula(XVIII) may be purchased from commercial sources or prepared by methodsknown to one skilled in the art. The compounds of formula (XIII) may beprepared using the methods described in connection with Schemes 1 and 2above.

In addition to the foregoing process for preparing certain compounds offormula (I), the present invention also provides certain intermediatecompounds for use in the preparation of such compounds of formula (I)according to the foregoing process. Thus, as one aspect, the presentinvention provides compounds of formula (XIX)

wherein all variables are as described above in connection with Scheme3.

In another aspect, the present invention provides compounds of formula(XX)

wherein all variables are as described above in connection with Scheme3.

Compounds of formula (I) wherein Y is CH or N, may be convenientlyprepared by the process outlined in Scheme 4 below.

wherein:

-   R¹ is selected from the group consisting of halo, —NR⁷R⁸, Ay,    —NR⁷Ay, Het, —NHR¹⁰Het, —NHHet and —NHR¹⁰Ay;    -   each R⁷ and R⁸ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        alkenyl, cycloalkenyl, —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹,        —R¹⁰C(O)R⁹, —C(O)R⁹, —C(O)R¹⁰Ay, —C(O)R¹⁰Het, —CO₂R⁹, —R¹⁰CO₂R⁹,        —C(O)NR⁹R¹¹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(O)Ay, —R¹⁰C(O)Het,        —C(S)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹,        —R¹⁰NHC(O)R¹⁰Het, —R¹⁰NHC(O)R¹⁰CO₂R⁹, —R¹⁰NHC(NCO₂R⁹)NHCO₂R⁹,        —R¹⁰NHC(O)NHSO₂R⁹, —R¹⁰NHC(O)NHSO₂Ay, —R¹⁰NHC(O)NHSO₂Het,        —R¹⁰C(NH)NR⁹R¹¹, —C(NH)NR⁹R¹¹, —SO₂NR⁹R¹¹, —R¹⁰SO₂NR⁹R¹¹,        —R¹⁰NHSO₂R⁹, —SO₂R¹⁰, —R¹⁰SO₂R¹⁰, —R¹⁰NHCOR⁹, —R¹⁰SO₂NHCOR⁹,        —R¹⁰NHP(O)(OR⁹)₂, —R¹⁰OP(O)(OR⁹)₂ and —R¹⁰OP(O)(OR¹⁰Ay)₂;    -   each R⁹ and R¹¹ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        —R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) where w is 1–10, and        —R¹⁰NR¹⁰R¹⁰;    -   each R¹⁰ is the same or different and is independently selected        from the group consisting of alkyl, cycloalkyl, alkenyl,        cycloalkenyl and alkynyl;    -   Ay is aryl;    -   Het is a 5- or 6-membered heterocyclic or heteroaryl group;-   R² is selected from the group consisting of halo, alkyl, cycloalkyl,    alkenyl, cycloalkenyl, —NR⁷R⁸, —OR⁷, —OAy, —S(O)_(n)R⁹, —S(O)_(n)Ay,    —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, Ay, Het, —NHHet, —NHR¹⁰Het, —OHet and    —OR¹⁰Het;-   n is 0, 1 or 2;-   Y is N or CH;-   R³ and R⁴ are the same or different and are each independently    selected from the group consisting of H, halo, alkyl, cycloalkyl,    alkenyl, Ay, —OR⁷, —OAy, —R¹⁰OR⁷, —R¹⁰OAy, —NR⁷R⁸, —NR⁷Ay,    —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —C(O)R⁷, —C(O)Ay, —CO₂R⁷, —CO₂Ay, —SO₂NHR⁹,    Het, —NHHet and —NHR¹⁰Het;-   q is 0, 1, 2, 3, 4 or 5;-   each R⁵ is the same or different and is independently selected from    the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, —R¹⁰cycloalkyl, Ay, —NHR¹⁰Ay, Het, —NHHet, —NHR¹⁰Het,    —OR⁷, —OAy, —OHet, —R¹⁰OR⁹, —NR⁷R⁸, —NR⁷Ay, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay,    —R¹⁰C(O)R⁹, C(O)R⁹, —CO₂R⁹, —R¹⁰CO₂R⁹, —C(O)NR⁷R⁸, —C(O)Ay,    —C(O)NR⁷Ay, —C(O)Het, —C(O)NHR¹⁰Het —R¹⁰C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹,    —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay,    —R¹⁰C(NH)NR⁹R¹¹, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰SO₂NHCOR⁹,    —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂R⁹, —S(O)_(n)R⁹, cyano, nitro and azido; or-    two adjacent R⁵ groups together with the atoms to which they are    bonded form a C₅₋₆ cycloalkyl or aryl;-   wherein when q is 1 and R⁵ is in the para position, R⁵ is not halo;-   wherein when Y is CH, R³ is not —NR⁷Ay;-   X¹ is chloro, bromo, or iodo; and-   M² is —B(OH)₂, —B(ORa)₂, —B(Ra)₂, —Sn(Ra)₃, Zn-halide, ZnRa, or    Mg-halide where Ra is alkyl or cycloalkyl and halide is halo.

Generally, the process for preparing compounds of formula (I) (allformulas and variables having been defined above in connection withScheme 4), comprises the following steps:

-   a) halogenating a compound of formula (XII) to prepare a compound of    formula (XXII); and-   b) reacting the compound of formula (XXII) with a compound of    formula (XXIV) to prepare the compounds of formula (I).

More specifically, compounds of formula (I) wherein Y is N or CH can beprepared by reacting a compound of formula (XXII) with a compound offormula (XXIV).

wherein all variables are as defined above in connection with Scheme 4.

The reaction may be carried out in an inert solvent, in the presence ofa palladium (0) or nickel (0) catalyst. The reaction may optionally beheated to about 50–150° C. Preferably the reaction is performed byreacting equimolar amounts of a compound of formula (XXII) with aHet-metal compound of formula (XXIV), but the reaction may also beperformed in the presence of an excess of compound of the formula(XXIV). The palladium or nickel catalyst is preferrably present in 1–10mol % compared to the compound of formula (XXII). Examples of suitablepalladium catalysts include but are not limited to,tetrakis(triphenylphosphine)palladium (0),dichlorobis(triphenyl-phosphine)palladium(II),tris(dibenzylideneacetone)dipalladium (0), andbis(diphenylphosphinoferrocene)palladium (II) dichloride. Suitablesolvents include but are not limited to, N,N-dimethylformamide, toluene,tetrahydrofuran, dioxane, and 1-methyl-2-pyrrolidinone. When theHet-metal compound of formula (XXIV) is an arylboronic acid or ester oran arylborinate the reaction is more conveniently carried out by addinga base in a proportion equivalent to, or greater than, that of thecompound of formula (XXIV). Het-metal compounds of formula (XXIV) may beobtained from commercial sources or prepared either as discreet isolatedcompounds or generated in situ using methods known to one skilled in theart. (Suzuki, A. J. Organomet. Chem. 1999, 576, 147; Stille, J. Angew.Chem. Int. Ed. Engl. 1986, 25, 508; Snieckus, V. J. Org. Chem. 1995, 60,292.)

Compounds of formula (XXII) can be prepared from compounds of formula(XII) by a halogenation procedure.

wherein all variables are as defined above in connection with Scheme 4.

Typically, the halogenation reaction is carried out by subjecting thecompounds of formula (XII) to a halogenating agent in a suitablesolvent. Suitable halogenating agents include but are not limited to,N-bromosuccinimide, trialkylammonium tribromides, bromine,N-chlorosuccinimide, N-iodosuccinimide, iodine monochloride, and thelike. Suitable solvents include, for example, N,N-dimethylformamide,tetrahydrofuran, dioxane, 1-methyl-2-pyrrolidinone, carbontetrachloride, toluene, dichloromethane, diethyl ether, and the like.

In the embodiments wherein the compound of formula (XXII) is definedwhere R¹ is chloro, (i.e., compounds of formula (XXII-A)) and compoundsof formula (I) where R¹ is other than chloro are desired, it may bedesireable to convert the compounds of formula (XXII-A) to compounds offormula (XXII-B) prior to reacting with the Het-metal compound offormula (XXIV). Compounds of formula (XXII-B) can be conveniently andsurprisingly prepared from compounds of formula (XXII-A) by an aminationprocedure.

wherein R¹³ is selected from the group consisting of —NR⁷R⁸, —NR⁷Ay,Het, —NHR¹⁰Het, —NHHet and —NHR¹⁰Ay, and all other variables are asdefined above in connection with Scheme 4.

The ability to replace the chlorine in preference to the bromine of theheterocyclic ring system is unexpected. Preferably, a compound offormula (XXII-A) is reacted with a primary or secondary amine havingsubstitutions corresponding to those of R¹, in the presence of apalladium catalyst and a base. The procedure represents a modificationof procedures found in the literature (Wolfe, J. P.; Buchwald, S. L. J.Org. Chem. 2000, 65, 1144) wherein amines are cross-coupled to arylhalides. Suitable palladium (0) catalysts include palladium(II) acetateand tris(dibenzylideneacetone) dipalladium (0). Suitable bases includesodium tert-butoxide and cesium carbonate. Solvents such as toluene maybe employed.

In addition to the foregoing process for preparing compounds of formula(I), the present invention also provides certain intermediate compoundsfor use in the preparation of compounds of formula (I) according to theforegoing process. Thus, as one aspect, the present invention providescompounds of formula (XXII)

wherein X¹ is chloro, bromo, or iodo, and all other variables are asdefined above in connection with Scheme 4.

As will be apparent to those skilled in the art, the compounds offormula (I) may be converted to other compounds of formula (I) usingtechniques well known in the art. For example, one method of convertingcompounds of formula (I) to other compounds of formula (I) comprises a)oxidizing the compound of formula (I-A) to prepare a compound of formula(I-B) and then b) optionally reacting a compound of formula (I-B) withan oxygen or amine nucleophile of formula R², wherein R² is selectedfrom the group consisting of —NR⁷R⁸, —OR⁷, —OAy, Het attached through N,—NHHet, —NHR¹⁰Het, —OHet and —OR¹⁰Het to produce a compound of formula Iwherein R² is selected from the group consisting of —NR⁷R⁸, —OR⁷, —OAy,Het attached through N, —NHHet, —NHR¹⁰Het, —OHet and —OR¹⁰Het.

wherein n′ is 1 or 2 and all other variables are as defined according toany of the processes described above.

More specifically, compounds of formula (I) can be prepared by reactinga compound of formula (I-B) (i.e., compounds of formula I wherein R² isS(O)_(n).R⁹ where n′ is 1 or 2) with an oxygen or amine nucleophile offormula R², wherein R² is selected from the group consisting of —NR⁷R⁸,—OR⁷, —OAy, Het linked through N, —NHHet, —NHR¹⁰Het, —OHet, and—OR¹⁰Het. The reaction may be carried out neat or in a suitable solventand may be heated to 50–150° C. Typically the solvent is a lower alcoholsuch as methanol, ethanol, isopropanol or the like or a solvent such asN,N-dimethylformamide or tetrahydrofuran, or the like. Optionally a basemay be used to facilitate the reaction. Typically the base can bepotassium carbonate, or an amine base such as triethylamine.

Compounds of formula (I-B) may be conveniently prepared by reacting acompound of formula (I-A) (i.e., compounds of formula I wherein R² isS(O)_(n)R⁹ where n is 0) with an oxidizing agent in an inert solvent,optionally in the presence of a base. Typically the oxidizing agent is aperacid such as m-chloroperbenzoic acid or the like optionally with abase such as sodium bicarbonate. Careful monitoring of the stoichiometrybetween the oxidizing agent and the substrate allows the productdistribution between sulfoxide (n=1), and sulfone (n=2) to becontrolled. Suitable solvents include but are not limited to,dichloromethane, chloroform and the like.

Compounds of formula (I-A) are prepared by methods described abovewherein R²=SR⁹ from the reaction of compounds selected from the groupconsisting of compounds of formula (XVI), compounds of formula (IX) andcompounds of formula (XX) with a compound of formula (X-A) (i.e., thecompound of formula (X) wherein R² is SR⁹). The requisite compound offormula (X-A) can be obtained from commercial sources or prepared bymethods known to one skilled in the art.

Another particularly useful method for converting compounds of formula(I) to other compounds of formula (I) comprises reacting a compound offormula (I-C) (i.e., a compound of formula (I) wherein R² is fluoro)with an amine, and optionally heating the mixture to 50–150° C. toprepare a compound of formula (I-D) (i.e., a compound of formula (I)wherein R² is NR⁷R⁸).

wherein all variables are as defined in connection with any of theprocesses described above.

This procedure may be carried out by mixing a compound of formula (I-C)in an amine neat, or in a suitable solvent with an excess of amine toproduce a compound of formula (I-D). Typically the solvent is a loweralcohol such as methanol, ethanol, isopropanol or the like. Othersuitable solvents may include N,N-dimethylformamide,1-methyl-2-pyrrolidine or the like.

As a further example, compounds of formula (I-E) may be converted tocompounds of formula (I-F) using either of two methods.

wherein M³ is B(OH)₂, B(ORa)₂, B(Ra)₂, Sn(Ra)₃, Zn-halide, Zn—Ra orMg-halide, where Ra is alkyl or cycloalkyl, halide is halo, and allother variables are as defined in connection with any process describedabove.

Such method can be carried out using the reaction and conditionsdescribed above in connection with Scheme 1 and the conversion ofcompounds of formula VII to compounds of formula VIII. Thus, the presentinvention provides a process for converting compounds of formula (I-E)to compounds of formula (I-F) which comprises either: (1) replacing theC-7 halogen of the compound of formula (I-E) with an amine; or (2)coupling the compound of formula (I-E) with an aryl metal of the formulaAy-M³ where M³ is B(OH)₂, B(ORa)₂, B(Ra)₂, Sn(Ra)₃, Zn-halide, Zn—Ra orMg-halide.

As a further example, compounds of formula (I-G) (i.e., compounds offormula (I) wherein q is 1 or more and at least one R⁵ is O-methyl) maybe converted to compounds of formula (I-H) (i.e., compounds of formula(I) wherein q is 1 or more and at least one R⁵ is OH) using conventionaldemethylation techniques. Additionally, compounds of formula (I-H) mayoptionally be converted to compounds of formula (I-J) (i.e., compoundsof formula (I) wherein q is 1 or more and at least one R⁵ is OR¹⁰). Forexample, the foregoing conversions are represented schematically asfollows:

wherein q′ is 0 1, 2, or 3, Me is methyl and all other variables are asdefined in connection with any process described above.

The demethylation reaction may be carried out by treating a compound offormula (I-G) in a suitable solvent with a Lewis acid at a temperatureof −78° C. to room temperature, to produce a compound of formula (I-H).Typically the solvent is an inert solvent such as dichloromethane,chloroform, acetonitrile, toluene and the like. The Lewis acid may beboron tribromide, trimethylsilyl iodide or the like.

Optionally, the compounds of formula (I-H) may be further converted tocompounds of formula (I-J) by an alkylation reaction. The alkylationreaction may be carried out by treating a compound of formula (I-H) insuitable solvent with an alkyl halide of formula R¹⁰-Halo where R¹⁰ isas defined above, to form another compound of formula (I-J). Thereaction is preferably carried out in the presence of a base and withoptionally heating to 50–200° C. The reaction may be carried out insolvents such as N,N-dimethylformamide, dimethylsulfoxide and the like.Typically the base is potassium carbonate, cesium carbonate, sodiumhydride or the like. Additionally, as will be apparent to those skilledin the art, the alkylation reaction can be carried out under Mitsunobuconditions.

As a further example of methods for converting compounds of formula (I)to other compounds of formula (I), compounds of formula (I-K) (i.e.,compounds of formula (I) wherein q is 1 or more and at least one R⁵ ishalo) may be converted to compounds of formula (I-L) (i.e., compounds offormula (I) wherein q is 1 or more and at least one R⁵ is Het) orcompounds of formula (I-M) (i.e., compounds of formula (I) wherein q is1 or more and at least one R⁵ is Ay). For example, the conversion ofcompounds of formula (I-K) to compounds of formula (I-L) or compounds offormula (I-M) is shown schematically below.

-   wherein q′ is 0, 1, 2 or 3;-   M⁴ is selected from the group consisting of —B(OH)₂, —B(ORa)₂,    —B(Ra)₂, and —Sn(Ra)₂ wherein Ra is alkyl or cycloalkyl; and all    other variables are as defined in connection with any of the    processes described above.

The conversion of compounds of formula (I-K) to compounds of formula(I-L) or (I-M) is carried out by coupling the compound of formula (I-K)with a compound of formula Het-M⁴ to make compounds of formula (I-L) ora compound of formula Ay-M⁴ to make compounds of formula (I-M). Thereaction may be carried out in an inert solvent, in the presence of apalladium (0) source. The reaction may optionally be heated to 50–150°C. Preferably the reaction is performed by reacting equimolar amounts ofa compound of formula (I-K) with a compound of formula Het-M⁴ or Ay-M⁴(depending upon whether compounds of formula (I-L) or compounds offormula (I-M) are desired). The reaction may also be performed in thepresence of an excess Het-M⁴ or Ay-M⁴. The palladium (0) catalyst ispreferrably present in 1–25 mol % compared to the compound of formula(I-K). Examples of suitable palladium catalysts include but are notlimited to, tetrakis(triphenylphosphine)palladium (0),dichlorobis(triphenyl-phosphine)palladium(II), andbis(diphenylphosphinoferrocene)palladium (II) dichloride. Suitablesolvents include but are not limited to, N,N-dimethylformamide, toluene,tetrahydrofuran, dioxane, and 1-methyl-2-pyrrolidinone. When thecompound of formula Het-M⁴ or Ay-M⁴ is a boronic acid or ester or aborinate the reaction is more conveniently carried out by adding a basein a proportion equivalent to, or greater than, that of the compound offormula Het-M⁴ or Ay-M⁴. Compounds of formula Het-M⁴ and Ay-M⁴ may beobtained from commercial sources or prepared either as discreet isolatedcompounds or generated in situ using methods known to one skilled in theart. (Suzuki, A. J. Orgonomet. Chem. 1999, 576, 147; Stille, J. Angew.Chem. Int. Ed. Engl. 1986, 25, 508; Snieckus, V. J. Org. Chem. 1995, 60,292.)

In yet another example, compounds of formula (I-K) (i.e., compounds offormula (I) wherein q is 1 or more and at least one R⁵ is halo) areconverted to compounds of formula (I-N) (i.e., compounds of formula (I)wherein q is 1 or more and at least one R⁵ is NH₂). Optionally,compounds of formula (I-N) may then be converted to compounds of formula(I-O) (i.e., compounds of formula (I) wherein q is 1 or more and atleast one R⁵ is —NR⁷R⁸). For example, the foregoing conversions arerepresented schematically as follows:

wherein q′ is 0, 1, 2 or 3 and all other variables are as defined abovein connection with any process described above.

The process of converting compounds of formula (I-K) to compounds offormula (I-N) is carried out by reacting a compound of formula (I-K)with an imine in the presence of a palladium (0) source, a base and asuitable ligand, followed by hydrolysis to give a compound of formula(I-N). See J. Wolfe, et al., Tetrahedron Letters 38:6367–6370 (1997).Typically the imine is benzophenoneimine, the palladium (0) source istris(dibenzylideneacetone)dipalladium(0), the base is sodiumtert-butoxide and the ligand isracemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl. Suitable solventsinclude N,N-dimethylformamide and the like.

Reaction of a compound of formula (I-N) with compound of formulaR⁷-halogen in a suitable solvent in the presence of base, optionallywith heating may be used to prepare compounds of formula (I-O).Typically the base is triethylamine or pyridine and the solvent isN,N-dimethylformamide and the like. Other transformations well known tothose skilled in the art for use with anilines may be used to convertcompounds of formula (I-N) to compounds of formula (I-O).

Additional compounds of formula (I-O) can be obtained by reductiveamination of compounds of formula (I-N) with ketones or aldehydes. See,A. Abdel-Magid, et al., J. Org. Chem. 61:3849–3862 (1996). Typically acompound of formula (I-N) is treated with an aldehyde or a ketone in thepresence of an acid, such as acetic acid, and a reducing agent, such assodium triacetoxyborohydride and the like, in an inert solvent such asdichloroethane and the like.

Based upon this disclosure and the examples contained herein one skilledin the art can readily convert compounds of formula (I) or apharmaceutically accetpable salt, solvate or physiologically functionalderivative thereof into other compounds of formula (I), orpharmaceutically acceptable salts, solvates or physiologicallyfunctional derivatives thereof.

The present invention also provides radiolabeled compounds of formula(I) and biotinylated compounds of formula (I) (e.g., examples 80 and 82below). Radiolabeled compounds of formula (I) and biotinylated compoundsof formula (I) can be prepared using conventional techniques. Forexample, radiolabeled compounds of formula (I) can be prepared byreacting the compound of formula (I) with tritium gas in the presence ofan appropriate catalyst to produce radiolabeled compounds of formula(I). Biotinylated compounds of formula (I) can be prepared using themethods described in examples 80 and 82 below.

In one preferred embodiment, the compounds of formula (I) are tritiated.

The radiolabeled compounds of formula (I) and biotinylated compounds offormula (I) are useful in assays for the identification of compounds forthe treatment or prophylaxis of viral infections such as herpes viralinfections. Accordingly, the present invention provides an assay methodfor identifying compounds which have activity for the treatment orprophylaxis of viral infections such as herpes viral infections, whichmethod comprises the step of specifically binding the radiolabeledcompound of formula (I) or the biotinylated compound of formula (I) tothe target protein. More specifically, suitable assay methods willinclude competition binding assays. The radiolabeled compounds offormula (I) or biotinylated compounds of formula (I) can be employed inassays according to the methods conventional in the art.

The following examples are intended for illustration only and are notintended to limit the scope of the invention in any way. Reagents arecommercially available or are prepared according to procedures in theliterature. Example numbers refer to those compounds listed in thetables above. ¹H and ¹³C NMR spectra were obtained on Varian Unity PlusNMR spectrophotometers at 300 or 400 MHz, and 75 or 100 MHzrespectively. ¹⁹F NMR were recorded at 282 MHz. Mass spectra wereobtained on Micromass Platform, or ZMD mass spectrometers from MicromassLtd. Altrincham, UK, using either Atmospheric Chemical Ionization (APCI)or Electrospray Ionization (ESI). Analytical thin layer chromatographywas used to verify the purity of some intermediates which could not beisolated or which were too unstable for full characterization, and tofollow the progress of reactions. Unless otherwise stated, this was doneusing silica gel (Merck Silica Gel 60 F254). Unless otherwise stated,column chromatography for the purification of some compounds, used MerckSilica gel 60 (230–400 mesh), and the stated solvent system underpressure. All compounds were characterized as their free-base formunless otherwise stated. On occasion the corresponding hydrochloridesalts were formed to generate solids where noted.

EXAMPLE 1N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)-pyrazolo[1,5-a]pyridin-7-amine

a) 2-(6-Chloro-2-pyridinyl)-1-(4-methoxyphenyl)ethanone

To a cold (0° C.) solution of 6-chloro-2-picoline (18.3 mL, 166.5 mmol)and ethyl 4-methoxybenzoate (30.0 g, 166.5 mmol) in tetrahydrofuran (300mL) was added lithium bis(trimethylsilyl)amide (333 mL, 1.0 M intetrahydrofuran, 332.7 mmol) dropwise via a pressure equalizing funnelover 1 hour. Upon complete addition, the cold bath was removed and theresulting solution was heated at 45° C. for hours. The mixture wascooled to room temperature, and the solution was concentrated. Methanolwas added to quench the reaction, resulting in the formation of a yellowprecipitate. The precipitate was collected by filtration and dried togive 2-(6-chloro-2-pyridinyl)-1-(4-methoxyphenyl)ethanone (37.4 g, 86%)as a yellow solid. ¹H NMR (CDCl₃): δ 7.99 (d, 2H), 7.57 (t, 1H),7.22–7.19 (m, 2H), 6.90 (d, 2H), 4.39 (s, 2H), 3.83 (s, 3H); MS m/z 262(M+1).

b) 2-(6-Chloro-2-pyridinyl)-1-(4-methoxyphenyl)ethanone oxime

To a solution of 2-(6-chloro-2-pyridinyl)-1-(4-methoxyphenyl)ethanone(37.4 g, 142.9 mmol) in methanol (500 mL) was added hydroxylaminehydrochloride (49.7 g, 714.5 mmol) followed by the addition of a sodiumhydroxide solution (28.6 g, 714.5 mmol in 50 mL of water). The resultingsuspension was heated at reflux for 2 hours and then allowed to cool toroom temperature. The mixture was concentrated and water was added tothe resulting slurry. A white precipitate formed, which was collected byfiltration, washed with water and dried to give2-(6-chloro-2-pyridinyl)-1-(4-methoxyphenyl)ethanone oxime (38.7 g, 97%)as a white solid. ¹H NMR (CDCl₃): δ 8.23 (b, 1H), 7.63 (d, 2H), 7.48 (d,1H), 7.12 (m, 2H), 6.83 (dd, 2H), 4.33 (s, 2H), 3.76 (s, 3H); MS m/z 277(M+1).

c) 7-Chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridine

To a solution of 2-(6-chloro-2-pyridinyl)-1-(4-methoxyphenyl)ethanoneoxime (38.7 g, 140 mmol) in 1,2-dimethoxyethane (150 mL) at 0° C. wasadded trifluoroacetic anhydride (20 mL, 140 mmol), keeping thetemperature below 10° C. during the addition. After the addition wascomplete, the reaction was warmed to 15° C. The solution was then cooledto 4° C. and a solution of triethylamine (39 mL, 280 mmol) in1,2-dimethoxyethane (15 mL) was added over a period of 0.5 hours. Themixture was allowed to warm to room temperature and was stirred at roomtemperature for 1.5 hours. To this mixture was added iron(II) chloride(0.18 g, 1.4 mmol) and the reaction was heated at 75° C. for 15 hours.The reaction mixture was poured into water (300 mL). The resultingsuspension was extracted with ethyl acetate. The organic phase was dried(magnesium sulfate), filtered and concentrated to a solid. This solidwas recrystallized from methanol to give7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridine (18.7 g, 52%) aspale yellow needles. ¹H NMR (CDCl₃): δ 7.91 (d, 2H), 7.43 (d, 1H), 7.01(t,1H), 6.95 (d, 2H), 6.81 (d, 1H), 6.80 (s, 1H), 3.83 (s, 3H); MS m/z259 (M+1).

d) 1-[7-(Chloro)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone

To a solution of 7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridine(18.7 g, 72.4 mmol) in toluene (300 mL) at room temperature was addedacetic anhydride (8.2 mL, 86.9 mmol). Boron trifluoride diethyletherate(10.1 mL, 79.6 mmol) was then added dropwise and the resulting solutionwas heated at reflux for 4 hours. The reaction mixture was cooled toroom temperature and quenched by the dropwise addition of saturatedaqueous sodium bicarbonate. The reaction was extracted with ethylacetate, and the ethyl acetate phase washed with brine, dried (magnesiumsulfate), filtered and concentrated. The residue was purified byrecrystallization from ethyl acetate-hexanes to give1-[7-(chloro)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone(14.2 g, 65%) as reddish needles. ¹H NMR (CDCl₃): δ 8.37 (dd, 1H), 7.49(dd, 2H), 7.39 (dd, 1H), 7.10 (dd, 1H), 6.98 (dd, 2H), 3.84 (s, 3H),2.13 (s, 3H); MS m/z 301 (M+1).

e)1-[7-(Cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone

To a solution of1-[7-(chloro)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone(5.0 g, 16.6 mmol) in toluene (100 mL) was added successivelyracemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (620 mg, 1.0 mmol),cesium carbonate (8.12 g, 24.9 mmol), cyclopentylamine (8.2 mL, 83.1mmol), and palladium (II) acetate (150 mg, 0.66 mmol). The resultingmixture was stirred at 95° C. for 4 hours, at which time the reactionwas judged complete by thin layer chromatography. The solution wascooled to room temperature and diethyl ether and water were added to thereaction mixture. The phases were separated, and the aqueous phase againextracted with diethyl ether. The combined organic phases were dried(magnesium sulfate), filtered and concentrated. The resulting residuewas purified by flash chromatography (4:1 hexanes:ethyl acetate) to give1-[7-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone(5.66 g, 97%) as a yellow foam. ¹H NMR (CDCl₃): δ 7.65 (d, 1H), 7.48 (d,2H), 7.39 (t, 1H), 6.99 (d, 2H), 6.09 (d, 1H), 6.01 (d, 1H), 3.95 (m,1H), 3.84 (s, 3H), 2.09 (s, 3H), 2.09–2.00 (m, 2H) 1.76–1.22 (m, 6H); MSm/z 350 (M+1).

f)(2E)-1-[7-(Cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one

A solution of1-[7-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone(5.56 g, 15.9 mmol) in N,N-dimethylformamide dimethyl acetal (25 mL) washeated at reflux for 5 days. The mixture was allowed to cool to roomtemperature. Water was added and the resulting mixture was extractedwith ethyl acetate. The organic phase was dried (magnesium sulfate),filtered and concentrated. The resulting residue was purified by flashchromatography (7:3 ethyl acetate:acetone) to give(2E)-1-[7-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one(5.97 g, 93%) as a colored syrup: ¹H NMR (CDCl₃): δ 7.96–7.59 (m, 3H),7.53 (d, 1H), 7.23 (dd, 1H), 6.93 (d, 2H), 5.97–5.94 (m, 2H), 5.07 (d,1H), 3.95 (m, 1H), 3.81 (s, 3H), 3.0–2.3 (b, 6H), 2.07 (m, 2H),1.76–1.60 (m, 2H); MS m/z 405 (M+1).

g)N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)-pyrazolo[1,5-a]pyridin-7-amine

To a solution of(2E)-1-[7-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one(5.97 g, 14.7 mmol) in dimethylformamide (80 mL) was added N-cyclopentylguanidine hydrochloride (4.33 g, 26.5 mmol; Prepared by modification ofa procedure from Bannard, R. A. B. et al., Can. J. Chem. 1958, 36,1541–1549), followed by potassium carbonate (2.03 g, 14.7 mmol). Theresulting solution was heated at reflux for 6 hours. Upon cooling toroom temperature, water was added. The mixture was extracted with ethylacetate. The ethyl acetate phase was washed with brine, dried (magnesiumsulfate), filtered and concentrated in vacuo. The resulting residue waspurified by flash chromatography (4:6 ethyl acetate:hexane) to giveN-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)-pyrazolo[1,5-a]pyridin-7-amine(5.02 g, 73%) as a yellow solid. ¹H NMR (CDCl₃): δ 7.95 (d, 1H), 7.72(d, 1H), 7.54 (dd, 2H), 7.25 (t, 1H), 6.94 (dd, 2H), 6.28 (d, 1H),6.00–5.97 (m, 2H), 5.03 (d, 1H), 4.33–4.31 (m, 1H), 3.96 (m, 1H), 3.83(s, 3H), 2.10–2.01 (m, 4H), 1.77–1.50 (m, 12H); MS m/z 469 (M+1); Anal.Calcd for C₂₈H₃₂N₆O: C, 71.77; H, 6.88; N17.93. Found: C, 71.41; H,7.02; N, 17.89.

EXAMPLE 2N-Cyclopentyl-4-[2-(4-methoxyphenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

a)1-[2-(4-Methoxyphenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone

In a similar manner as described in Example 1 from1-[7-(chloro)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone(5.00 g, 16.6 mmol) and pyrrolidine,1-[2-(4-methoxyphenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone(4.68 g, 84%) was obtained as a yellow crystalline solid. ¹H NMR(CDCl₃): δ 7.79 (d, 1H), 7.50 (dd, 2H), 7.33 (t, 1H), 6.97 (dd, 2H),6.12 (d, 1H), 3.84 (s, 3H), 3.74–3.70 (m, 4H), 2.11 (s, 3H), 1.99–1.95(m, 4H); MS m/z 336 (M+1).

b)(2E)-3-(Dimethylamino)-1-[2-(4-methoxyphenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propen-1-one

In a similar manner as described in Example 1 from1-[2-(4-methoxyphenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone(4.0 g, 11.9 mmol),(2E)-3-(dimethylamino)-1-[2-(4-methoxyphenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propen-1-one(4.18 g, 90%) was obtained as a brown syrup. ¹H NMR (CDCl₃): δ 7.76 (d,1H), 7.65 (dd, 2H), 7.53 (d, 1H), 7.20 (t, 1H), 6.93 (dd, 2H), 6.03 (d,1H), 5.13 (d, 1H), 3.81 (s, 3H), 3.71–3.68 (m, 4H), 3.10–2.35 (b, 6H),2.00–1.96 (m, 4H); MS m/z 391 (M+1).

c)N-Cyclopentyl-4-[2-(4-methoxyphenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

In a similar manner as described in Example 1 from(2E)-3-(dimethylamino)-1-[2-(4-methoxyphenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propen-1-one(500 mg, 1.28 mmol),N-cyclopentyl-4-[2-(4-methoxyphenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(420 mg, 70%) was obtained as a solid. ¹H NMR (CDCl₃): δ 7.97 (d, 1H),7.84 (d, 1H), 7.57 (d, 2H), 7.19 (t,1H), 6.91 (d, 2H), 6.33 (d, 1H),6.04 (d1H), 4.99 (d, 1H), 4.33 (m, 1H), 3,82 (s, 3H), 3.73–3.70 (m, 4H),2.07–1.97 (m, 6H), 1.73–1.48 (m, 6H); MS m/z 455 (M+1); Anal. Calcd forC₂₇H₃₀N₆O: C, 71.34; H, 6.65; N18.49. Found: C, 71.58; H, 6.73; N,18.28.

EXAMPLE 34-[2-(4-Methoxyphenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

To a solution of(2E)-3-(dimethylamino)-1-[2-(4-methoxyphenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propen-1-one(500 mg, 1.28 mmol) in dimethylformamide (10 mL) was added guanidinesulfate (277 mg, 1.28 mmol), followed by potassium carbonate (195 mg,1.41 mmol). The resulting solution was heated at reflux for 6 hours.After cooling to room temperature, ethyl acetate and water were added.The phases were separated and aqueous phase extracted with additionalethyl acetate. The combined organics were dried (magnesium sulfate),filtered and concentrated in vacuo to give4-[2-(4-methoxyphenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(440 mg, 89%) as a yellow solid. ¹H NMR (CDCl₃): δ 7.98 (d, 1H), 7.80(d, 1H), 7.56 (dd, 2H), 7.20 (t, 1H), 6.92 (d, 2H), 6.43 (d, 1H), 6.05(d, 1H), 4.95 (b, 2H), 3.83 (s, 3H), 3.74–3.70 (m, 4H), 2.01–1.98 (m,4H); MS m/z 387 (M+1).

EXAMPLE 44-{7-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo-[1,5-a]pyridin-2-yl}phenol

To a solution ofN-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine(1.16 g, 2.48 mmol) in dichloromethane (50 mL) at −78° C. was addedboron tribromide (9.92 mL, 1.0 M in dichloromethane, 9.92 mmol)dropwise. The resulting solution was allowed to warm to roomtemperature. After stirring for 15 hours at room temperature, themixture was cooled to 0° C. and quenched by the addition of water. Themixture was extracted with ethyl acetate. The organic phase was dried(magnesium sulfate), filtered and concentrated to give a solid residuewhich was purified by flash chromatography (95:5 chloroform-methanol).4-{7-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenolwas obtained as a yellow solid (0.80 g, 71%). ¹H NMR (CDCl₃): δ 7.91 (d,1H), 7.70 (d, 1H), 7.46 (d, 2H), 7.26 (t, 1H), 6.86 (d, 2H), 6.27 (d,1H), 6.00–5.97 (m, 2H), 5.06 (d, 1H), 4.33 (m, 1H), 3.96 (m, 1H),2.10–2.03 (m, 4H), 1.78–1.47 (m, 12H); MS m/z 455 (M+1). U157430-190

EXAMPLE 54-[3-[2-(Cyclopentylamino)-4-pyrimidinyl]-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenol

In a similar manner as described in Example 4 fromN-cyclopentyl-4-[2-(4-methoxyphenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(300 mg, 0.66 mmol) was obtained4-[3-[2-(cyclopentylamino)-4-pyrimidinyl]-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenol(190 mg, 66%) as an orange solid. ¹H NMR (CD₃OD): δ 7.74 (d, 1H), 7.63(d, 1H), 7.33 (dd, 2H), 7.10 (t, 1H), 6.79 (dd, 2H), 6.23 (d, 1H), 5.84(d, 1H), 4.20–4.12 (m, 1H), 3.52 (m, 1H), 3.30–3.27 (m, 2H), 3.13–3.10(m, 2H), 1.95–1.41 (m, 12H); MS m/z 441 (M+1).

EXAMPLE 64-[3-(2-Amino-4-pyrimidinyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenol

In a similar manner as described in Example 4 from4-[2-(4-methoxyphenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(310 mg, 0.80 mmol) was obtained4-[3-(2-amino-4-pyrimidinyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenol(180 mg, 60%) as a yellow solid. ¹H NMR (d₆-DMSO): δ 9.68 (s, 1H),7.95–7.90 (m, 2H), 7.40 (d, 2H), 7.28 (t, 1H), 6.84 (d, 2H), 6.51 (b,2H), 6.23–6.17 (m, 2H), 3.72–3.70 (m, 4H), 1.99–1.92 (m, 4H); MS m/z 373(M+1).

EXAMPLE 72-[4-(Allyloxy)phenyl]-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine

To a solution of4-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenol(100 mg, 0.22 mmol) in N,N-dimethylformamide (5 mL) was added allylbromide (21 μL, 0.24 mmol) and potassium carbonate (122 mg, 0.88 mmol).The mixture was heated at reflux for 3 hours. The mixture was allowed tocool to room temperature and water was added. The mixture was extractedwith ethyl acetate. The ethyl acetate phase was dried (magnesiumsulfate), filtered and concentrated to a solid. The residue was purifiedby flash chromatography (1:1 ethyl acetate:hexanes) to give2-[4-(allyloxy)phenyl]-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine(67 mg, 61%) as a yellow solid. ¹H NMR (CDCl₃): δ 7.94 (d, 1H), 7.73 (d,1H), 7.53 (d, 2H), 7.24 (t, 1H), 6.95 (d, 2H), 6.28 (d, 1H), 6.08–5.96(m, 3H), 5.41 (dd, 1H), 5.27 (dd, 1H), 5.10 (d, 1H), 4.56 (d, 2H), 4.32(m, 1H), 3.95 (m, 1H), 2.10–2.00 (m, 4H), 1.76–1.45 (m, 12H); MS m/z 495(M+1); Anal. Calcd for C₃₀H₃₄N₆O: C, 72.86; H, 6.93; N16.99. Found: C,72.47; H, 7.05; N, 16.75.

EXAMPLE 8 Ethyl(4-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]-pyrazolo[1,5-a]pyridin-2-yl}phenoxy)acetate

To a solution of4-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenol(100 mg, 0.22 mmol) in acetone (10 mL) was added ethyl α-bromoacetate(49 μL, 0.44 mmol) and potassium carbonate (304 mg, 2.2 mmol). Themixture was heated to reflux for 3 hours. The reaction mixture wascooled to room temperature and water was added. The solution wasextracted with ethyl acetate. The organics were dried (magnesiumsulfate), filtered and concentrated, followed by purification with flashchromatography (1:1 ethyl acetate:hexanes) to give ethyl(4-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenoxy)acetate(85 mg, 71%) as a brown oil. ¹H NMR (CDCl₃): δ 7.94 (d, 1H), 7.70 (d,1H), 7.55 (d, 2H), 7.23 (t, 1H), 6.95 (d, 2H), 6.25 (d, 1H), 5.98–5.95(m, 2H), 5.13 (d, 1H), 4.62 (s, 2H), 4.31–4.21 (m, 3H), 3.94 (m, 1H),2.07–1.99 (m, 4H), 1.75–1.46 (m, 12H), 1.28 (t, 3H); MS m/z 541 (M+1).

EXAMPLE 92-(4-Butoxyphenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-pyrazolo[1,5-a]pyridin-7-amine

In a similar manner as described in Example 7 from4-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenol(100 mg, 0.22 mmol) and butyl bromide was formed2-(4-butoxyphenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine(80 mg, 71%) as a yellow solid. ¹H NMR (CDCl₃): δ 8.00 (d, 1H), 7.78 (d,1H), 7.57 (d, 2H), 7.28 (t, 1H), 6.97 (d, 2H), 6.34 (d, 1H), 6.05 (d,1H), 6.00 (d, 1H), 5.22 (d, 1H), 4.37 (m, 1H), 4.02 (m, 3H), 2.12–2.05(m, 4H), 1.82–1.49 (m, 16H), 1.00 (t, 3H); MS m/z 511 (M+1). EXAMPLE 10

N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-isobutoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine

In a similar manner as described in Example 7 from4-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenol(100 mg, 0.22 mmol) and isobutyl bromide was formedN-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-isobutoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine(76 mg, 68%) as a yellow foam. ¹H NMR (CDCl₃): δ 8.00 (d, 1H), 7.78 (d,1H), 7.57 (d, 2H), 7.29 (t, 1H), 6.98 (d, 2H), 6.35 (d, 1H), 6.05 (d,1H), 6.01 (d, 1H), 5.16 (d, 1H), 4.37 (m, 1H), 4.00 (m, 1H), 3.79 (d,2H), 2.16–2.05 (m, 5H), 1.81–1.52 (m, 12H), 1.06 (d, 6H); MS m/z 511(M+1).

EXAMPLE 11N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[4-(cyclopropyl-methoxy)phenyl]pyrazolo[1,5-a]pyridin-7-amine

In a similar manner as described in Example 7 from4-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenol(100 mg, 0.22 mmol) and (bromomethyl)cyclopropane was formedN-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[4-(cyclopropylmethoxy)phenyl]-pyrazolo[1,5-a]pyridin-7-amine(48 mg, 44%) as a yellow foam. ¹H NMR (CDCl₃): δ 7.99 (d, 1H), 7.77 (d,1H), 7.57 (dd, 2H), 7.30 (t, 1H), 6.97 (d, 2H), 6.33 (d, 1H), 6.04–6.00(m, 2H), 5.08 (d, 1H), 4.37 (m, 1H), 4.00 (m, 1H), 3.87 (d, 2H),2.14–2.07 (m, 4H), 1.82–1.52 (m, 12H), 1.32 (m, 1H), 0.65 (m, 2H), 0.38(m, 2H); MS m/z 509 (M+1).

EXAMPLE 122-[4-(Cyclobutylmethoxy)phenyl]-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine

In a similar manner as described in Example 7from4-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenol(67 mg, 0.15 mmol) and (bromomethyl)cyclobutane was formed2-[4-(cyclobutylmethoxy)phenyl]-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine(50 mg, 65%) as a yellow foam. ¹H NMR (CDCl₃): δ 7.99 (d, 1H), 7.78 (d,1H), 7.57 (d, 2H), 7.30 (t, 1H), 6.98 (d, 2H), 6.34 (d, 1H), 6.05–6.00(m, 2H), 5.13 (d, 1H), 4.37 (m, 1H), 3.99 (m, 3H), 2.82 (m, 1H),2.20–1.50 (m, 22H); MS m/z 523 (M+1).

EXAMPLE 13N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine

To a solution of4-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenol(100 mg, 0.22 mmol) in dichloromethane (5 mL) was added copper (II)acetate (40 mg, 0.22 mmol), phenylboronic acid (80 mg, 0.66 mmol),triethylamine (92 μL, 0.66 mmol) and molecular sieves. The mixture wasstirred at room temperature for 24 hours. Solids were removed byfiltration and the filtrate was concentrated, followed by purificationby flash chromatography (2:3 ethyl acetate:hexanes) to giveN-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine(14 mg, 12%) as a yellow foam. ¹H NMR (CDCl₃): δ 8.05–6.85 (m, 12 H),6.40 (d, 1H), 6.06 (m, 2H), 5.12 (d, 1H), 4.40 (m, 1H) 4.01 (m, 1H),2.20–2.09 (m, 4H), 1.82–1.59 (m, 12H); MS m/z 531 (M+1).

EXAMPLE 142-(4-Bromophenyl)-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]pyrazolo-[1,5-a]pyridin-7-amine

a) 1-(4-Bromophenyl)-2-(6-chloro-2-pyridinyl)ethanone

In a similar manner as described in Example 1, from ethyl4-bromobenzoate (12.8 mL, 78.3 mmol) and 6-chloro-2-picoline (4.3 mL,39.2 mmol), 1-(4-bromophenyl)-2-(6-chloro-2-pyridinyl)ethanone (9.6 g,82%) was obtained as a crystalline solid existing as a keto-enoltautomeric mixture. ¹H NMR (CDCl₃): for the keto tautomer δ 7.95 (d,2H), 7.74–7.56 (m, 3H), 7.27 (m, 2H), 4.47 (s, 2H); MS m/z 310 (M+1).

b) 1-(4-Bromophenyl)-2-(6-chloro-2-pyridinyl)ethanone oxime

In a similar manner as described in Example 1, from1-(4-bromophenyl)-2-(6-chloro-2-pyridinyl)ethanone (9.5 g, 30.6 mmol)was obtained 1-(4-bromophenyl)-2-(6-chloro-2-pyridinyl)ethanone oxime(10.0 g, 99%) as a white solid. ¹H NMR (CDCl₃): δ 9.78 (broad s, 1H),7.74–7.47 (m, 5 H), 7.21–7.17 (m, 2H), 4.39 (s, 2 H); MS m/z 325 (M+1).

c) 2-(4-Bromophenyl)-7-chloropyrazolo[1,5-a]pyridine

In a similar manner as described in Example 1, from1-(4-bromophenyl)-2-(6-chloro-2-pyridinyl)ethanone oxime (45.2 g, 139mmol), 2-(4-bromophenyl)-7-chloropyrazolo[1,5-a]pyridine (30.5 g, 72%)was obtained as a pale yellow crystalline solid. 1H NMR (CDCl₃): δ 7.85(dd, 2 H), 7.54 (dd, 2 H), 7.46 (d, 1 H), 7.04 (m, 1 H), 6.87 (m, 2 H);MS m/z 307 (M+1).

d) 1-[2-(4-Bromophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]ethanone

In a similar manner as described in Example 1, from2-(4-bromophenyl)-7-chloropyrazolo[1,5-a]pyridine (10.0 g, 32.5 mmol),1-[2-(4-bromophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]ethanone (7.63g, 67%) was obtained as pink needles. ¹H NMR (CDCl₃): δ 8.37 (d, 1 H),7.62 (d, 2 H), 7.43 (m, 3 H), 7.14 (d, 1 H), 2.13 (s, 3 H); MS m/z 349(M+1).

e)1-[2-(4-Bromophenyl)-7-(butylamino)pyrazolo[1,5-a]pyridin-3-yl]ethanone

In a similar manner as described in Example 1, from1-[2-(4-bromophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]ethanone (2.55g, 7.3 mmol) and butylamine,1-[2-(4-bromophenyl)-7-(butylamino)pyrazolo[1,5-a]pyridin-3-yl]ethanone(2.15 g, 76%) was obtained as a yellow oil. ¹H NMR (CDCl₃): δ 7.61 (m, 3H), 7.43 (m, 3 H), 6.08 (d, 1 H), 6.02 (broad s, 1 H), 3.33 (q, 2 H),2.12 (s, 3 H), 1.70 (m, 2 H), 1.44 (m, 2 H), 0.94 (t, 3 H); MS m/z 386(M+1).

f)(2E)-1-[2-(4-Bromophenyl)-7-(butylamino)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one

In a similar manner as described in Example 1, from1-[2-(4-bromophenyl)-7-(butylamino)pyrazolo[1,5-a]pyridin-3-yl]ethanone(5.5 g, 14.2 mmol),(2E)-1-[2-(4-bromophenyl)-7-(butylamino)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one(5.78 g, 92%) was obtained as a brown oil. ¹H NMR (CDCl₃): δ 7.57 (m, 6H), 7.28 (t, 1 H), 5.95 (m, 2 H), 5.03 (d, 1 H), 3.32 (q, 2 H), 2.92(broad s, 3 H), 2.52 (broad s, 3 H), 1.71 (m, 2 H), 1.44 (m, 2 H), 0.94(t, 3 H); MS m/z 441 (M+1).

g)2-(4-Bromophenyl)-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine

In a similar manner as described in Example 1, from(2E)-1-[2-(4-bromophenyl)-7-(butylamino)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one(5.78 g, 13.1 mmol) and N-butylguanidine sulfate (Weiss, S.; Krommer, H.Chem.-Zgt. 1974, 98, 617–618) was obtained2-(4-bromophenyl)-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine(5.18 g, 80%) as a pale yellow solid. ¹H NMR (CDCl₃): δ 7.98 (d, 1 H),7.71 (d, 1 H), 7.56 (m, 4 H), 7.33 (t, 1 H), 6.35 (d, 1 H), 6.03 (m, 2H), 3.46 (q, 2 H), 3.38 (q, 2 H), 1.81–1.40 (m, 8 H), 0.98 (m, 6 H); MSm/z 493 (M+1).

EXAMPLE 152-[1,1′-Biphenyl]-4-yl-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]pyrazolo-[1,5-a]pyridin-7-amine

To a solution of2-(4-Bromophenyl)-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]pyrazolo-[1,5-a]pyridin-7-amine(52 mg, 0.11 mmol) in tetrahydrofuran was added phenylboronic acid (26mg, 0.21 mmol), sodium carbonate (0.21 mL, 2 M aqueous, 0.42 mmol), anddichlorobistriphenylphosphine palladium (II) (7.5 mg, 0.01 mmol). Themixture was heated at reflux for 3.5 hours. The resultant solution wascooled to room temperature and diluted with ether and water was added.The organic layer was washed with brine. The aqueous layer was extractedwith ether and the combined organics dried over magnesium sulfate.Filtration and concentration followed by flash chromatography provided2-[1,1′-biphenyl]-4-yl-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine(37 mg, 73%) as a yellow solid. ¹H NMR (CDCl₃): δ 8.05 (d, 1 H),7.83–7.69 (m, 7 H), 7.51 (m, 2 H), 7.43–7.33 (m, 2 H), 6.44 (d, 1 H),6.12 (t, 1 H), 6.05 (d, 1 H), 5.16 (broad, 1 H), 3.52 (m, 2 H), 3.42 (m,2 H), 1.84–1.43 (m, 8 H), 1.05–0.99 (m, 6 H); MS m/z 491 (M+1).

EXAMPLE 16N-{4-[2-(4-Aminophenyl)-7-(butylamino)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-butylamine

a)N-Butyl-3-[2-(butylamino)-4-pyrimidinyl]-2-{4-[(diphenylmethylene)-amino]phenyl}pyrazolo[1,5-a]pyridin-7-amine

To a solution of2-(4-bromophenyl)-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine(1.0 g, 2.0 mmol) in toluene (20 mL) was addedracemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (200 mg, 0.30 mmol),tris(dibenzylideneacetone)dipalladium(0) (92 mg, 0.10 mmol),diphenylimine (1.02 mL, 6.1 mmol), and sodium tert-butoxide (582 mg, 6.1mmol). The mixture was heated to 100° C. for 50 minutes. The resultantsolution was cooled to room temperature and diluted with ether and waterwas added. The organic layer was washed with brine. The aqueous layerwas extracted with ether and the combined organics dried over magnesiumsulfate. Filtration and concentration followed by flash chromatography(4:1 hexanes:ethyl acetate with 1% triethylamine) providedN-butyl-3-[2-(butylamino)-4-pyrimidinyl]-2-{4-[(diphenylmethylene)amino]phenyl}-pyrazolo[1,5-a]pyridin-7-amine(1.0 g, 84%) as a yellow solid. ¹H NMR (CDCl₃): δ 7.90 (d, 1 H),7.80–7.28 (m, 12 H), 7.19–7.16 (m, 2 H), 6.80 (d, 2 H), 6.07 (d, 1 H),6.02 (t, 1 H), 5.97 (d, 1 H), 4.99 (t, 1 H), 3.48 (m, 2 H), 3.36 (m, 2H), 1.80–1.43 (m, 8 H), 1.00–0.96 (m, 6 H); MS m/z 594 (M+1).

b)N-{4-[2-(4-Aminophenyl)-7-(butylamino)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-butylamine

To a solution ofN-butyl-3-[2-(butylamino)-4-pyrimidinyl]-2-{4-[(diphenylmethylene)-amino]phenyl}pyrazolo[1,5-a]pyridin-7-amine(1.0 g, 1.7 mmol) in tetrahydrofuran (50 mL) was added hydrochloric acid(10 mL, 4 N aqueous). The resultant solution was stirred at roomtemperature for 30 minutes. Ether was added and the solution was madebasic by the slow addition of saturated aqueous sodium bicarbonate. Theorganic layer was washed with brine. The aqueous layer was extractedwith ether and the combined organics dried over magnesium sulfate.Filtration and concentration followed by flash chromatography (1:1hexanes:ethyl acetate) providedN-{4-[2-(4-aminophenyl)-7-(butylamino)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-butylamineas an orange oil. ¹H NMR (CDCl₃): δ 8.02 (d, 1 H), 7.81 (d, 1 H), 7.47(d, 2 H), 7.31 (m, 1 H), 6.77 (d, 2 H), 6.42 (d, 1 H), 6.08 (m, 1 H),6.00 (d, 1 H), 5.18 (broad, 1 H), 3.86 (broad, 2 H), 3.53 (m, 2 H), 3.39(m, 2 H), 1.82–1.64 (m, 4 H), 1.58–1.46 (m, 4 H), 1.04–0.99 (m, 6 H); MSm/z430 (M+1). This material was treated with anhydrous hydrochloric acidin ether to provide the corresponding hydrochloride salt.

EXAMPLE 17N-Butyl-3-[2-(butylamino)-4-pyrimidinyl]-2-[4-(cyclohexylamino)phenyl]-pyrazolo[1,5-a]pyridin-7-amine

A solution ofN-{4-[2-(4-aminophenyl)-7-(butylamino)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-butylamine(62 mg, 0.15 mmol) in 1,2-dichloroethane (2 mL) was treated withcyclohexanone (0.02 mL, 0.22 mmol), acetic acid (0.04 mL, 0.72 mmol),and sodium triacetoxyborohydride (61 mg, 0.29 mmol). The resultantsolution was stirred at room temperature for 18 hours. Saturated aqueoussodium bicarbonate was added dropwise followed by ether. The organiclayer was washed with brine. The aqueous layer was extracted with etherand the combined organics dried over magnesium sulfate. Filtration andconcentration followed by flash chromatography (4:1 to 2:1 hexanes-ethylacetate) providedN-butyl-3-[2-(butylamino)-4-pyrimidinyl]-2-[4-(cyclohexylamino)phenyl]pyrazolo[1,5-a]pyridin-7-amine(54 mg, 73%) as an orange oil. ¹H NMR (CDCl₃): δ 7.94 (d, 1 H), 7.73 (d,1 H), 7.39 (d, 2 H), 7.23 (m, 1 H), 6.59 (d, 2 H), 6.41 (d, 1 H), 6.03(m, 1 H), 5.91 (d, 1 H), 5.11 (broad, 1 H), 3.66 (broad, 1 H), 3.44 (m,2 H), 3.30 (m, 3 H), 2.05 (m, 2 H), 1.75–1.12 (m, 16 H), 0.95–0.92 (m, 6H); MS m/z 512 (M+1). This material was treated with anhydroushydrochloric acid in ether to provide the corresponding hydrochloridesalt.

EXAMPLE 18N-Butyl-3-[2-(butylamino)-4-pyrimidinyl]-2-(4-isopropenylphenyl)-pyrazolo[1,5-a]pyridin-7-amine

To a cold (−78° C.) solution of 9-methoxy-9-borabicyclo[3.3.1]nonane (1mL, 1.0 M in hexane, 1.0 mmol) in tetrahydrofuran (5 mL) was addedisopropenylmagnesium bromide (2.0 mL, 0.5 M in tetrahydrofuran, 1.0mmol) dropwise. The resultant solution was stirred at −78° C. for 5minutes, then allowed to warm to room temperature. After 1 hour,potassium phosphate (0.33 mL, 3 M aqueous, 1.0 mmol) was added followedby N,N-dimethylformamide (5 mL),2-(4-Bromophenyl)-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine(100 mg, 0.20 mmol), and bis(diphenylphosphinoferrocene)palladium(II)chloride dichloromethane complex (17 mg, 0.02 mmol). The resultantsolution was stirred for 72 hours at room temperature. Ether was addedfollowed by water. The organic layer was washed with brine. The aqueouslayer was extracted with ether and the combined organics dried overmagnesium sulfate. Filtration and concentration followed by flashchromatography (6:1 to 4:1 to 2:1 hexanes:ethyl acetate) provided impureproduct. This material was taken up in tetrahydrofuran, cooled to 0° C.and 1 mL each of 10% aqueous sodium hydroxide and 30% hydrogen peroxidewere added. After 30 minutes, the mixture was quenched with saturatedaqueous sodium thiosulfate. Aqueous workup as reported above followed bysimilar chromatography providedN-butyl-3-[2-(butylamino)-4-pyrimidinyl]-2-(4-isopropenylphenyl)pyrazolo[1,5-a]pyridin-7-amine(25 mg, 27%) as an oil. ¹H NMR (CDCl₃): δ 8.00 (d, 1 H), 7.76 (d, 1 H),7.62 (d, 2 H), 7.54 (d, 2 H), 7.30 (m, 1 H), 6.35 (d, 1 H), 6.07 (m, 1H), 5.99 (d, 1 H), 5.46 (s, 2 H), 5.22 (broad, 1 H), 5.14 (s,1 H), 3.47(m, 2 H), 3.36 (m, 2 H), 2.20 (s, 3 H), 1.77–1.42 (m, 8 H), 1.00–0.95 (m6 H); MS m/z 455 (M+1). This material was treated with anhydroushydrochloric acid in ether to provide the corresponding hydrochloridesalt.

EXAMPLE 192-(4-Anilinophenyl)-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine

In a similar manner as described in Example 16 fromN-{4-[2-(4-bromophenyl)-7-(butylamino)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-butylamine(0.25 g, 0.5 mmol) aniline and sodium t-butoxide was prepared2-(4-anilinophenyl)-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine(16.5 mg, 6.4%) as a yellow solid. ¹H NMR (CDCl₃): δ 7.85 (broad, 1 H),7.74 (d, 1 H), 7.49 (d, 2 H), 7.29 (m, 3 H), 7.11 (m, 4 H), 6.95 (t, 1H), 6.40 (d, 1 H), 6.04 (t, 1 H), 6.00 (d, 1 H), 5.84 (s, 1 H), 3.49 (q,2 H), 3.34 (q, 2 H), 1.74–1.41 (m, 8 H), 0.95 (m, 6 H); MS m/z 505(M+1).

EXAMPLE 202-(4-Anilinophenyl)-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]-N-phenylpyrazolo[1,5-a]pyridin-7-amine

A mixture ofN-{4-[2-(4-aminophenyl)-7-(butylamino)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-butylamine(50 mg, 0.12 mmol), phenylboronic acid (43 mg, 0.35 mmol), copper(II)acetate (42 mg, 0.23 mmol), triethylamine (49 μL, 0.35 mmol) anddichloromethane (1 mL) was stirred at room temperature for 60 hours,then filtered and concentrated. Flash column chromatography eluting with3:1 hexanes:ethyl acetate afforded2-(4-anilinophenyl)-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]-N-phenylpyrazolo[1,5-a]pyridin-7-amine(29.8 mg, 44%) as a pale yellow solid. ¹H NMR (CDCl₃): δ 8.18 (d, 1 H),8.02 (d, 1 H), 7.42 (d, 2 H), 7.27–7.16 (m, 5 H), 7.09 (d, 2 H), 7.01(d, 2 H), 6.94–6.83 (m, 4 H), 6.66 (d, 1 H), 6.47 (d, 1 H), 5.78 (s, 1H), 5.21 (broad s, 1 H), 3.90 (m, 2 H), 3.48 (q, 2 H), 1.71–1.32 (m, 8H), 0.95 (t, 3 H), 0.88 (t, 3 H); MS m/z 582 (M+1).

EXAMPLE 212-{4-[Bis(cyclopropylmethyl)amino]phenyl}-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amineand EXAMPLE 22N-butyl-3-[2-(butylamino)-4-pyrimidinyl]-2-{4-[(cyclopropylmethyl)amino]phenyl}pyrazolo[1,5-a]pyridin-7-amine

To a solution ofN-{4-[2-(4-aminophenyl)-7-(butylamino)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-butylamine(64 mg, 0.15 mmol) in 1,2-dichloroethane (4 mL) was addedcyclopropanecarboxaldehyde (17 μL, 0.22 mmol), acetic acid (43 μL, 0.74mmol) and sodium triacetoxyborohydride (63 mg, 0.30 mmol). The reactionwas stirred at room temperature for 15 minutes, then quenched withaqueous sodium bicarbonate. The mixture was extracted with diethylether. The organic layer was dried over magnesium sulfate andconcentrated. Flash column chromatography eluting with a gradient of 10%to 25% ethyl acetate in hexanes afforded2-{4-[bis(cyclopropylmethyl)amino]phenyl}-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine(26.1 mg, 33%) as a gold solid: ¹H NMR (CDCl₃): δ 7.96 (d, 1 H), 7.78(d, 1 H), 7.50 (d, 2 H), 7.30 (t, 1 H), 6.87 (d, 2 H), 6.50 (d, 1 H),6.08 (t, 1 H), 5.99 (d, 1 H), 3.53 (q, 2 H), 3.40–3.33 (m, 6 H),1.79–1.46 (m, 8 H), 1.12 (m, 2 H), 0.99 (t, 6 H), 0.55 (m, 4 H), 0.26(m, 4 H); MS m/z 538 (M+1); andN-butyl-3-[2-(butylamino)-4-pyrimidinyl]-2-{4-[(cyclopropylmethyl)amino]-phenyl}pyrazolo[1,5-a]pyridin-7-amine(33.3 mg, 46%) as a yellow solid: ¹H NMR (CDCl₃): δ 7.85 (d, 1 H), 7.79(d, 1 H), 7.44 (d, 2 H), 7.33 (t, 1 H), 6.68 (d, 2 H), 6.43 (d, 1 H),6.09 (t, 1 H), 6.02 (d, 1 H), 3.54 (q, 2 H), 3.37 (q, 2 H), 3.03 (d, 2H), 1.80–1.43 (m, 8 H), 1.14 (m, 1 H), 0.99 (t, 6 H), 0.59 (m, 2 H),0.28 (m, 2 H); MS m/z 484 (M+1).

EXAMPLE 23N-Butyl-3-[2-(butylamino)-4-pyrimidinyl]-2-[4-(dimethylamino)phenyl]-pyrazolo[1,5-a]pyridin-7-amine

In a similar manner as described in Example 17 fromN-{4-[2-(4-aminophenyl)-7-(butylamino)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-butylamine(50 mg, 0.12 mmol), formaldehyde (13 μL, 37% aqueous solution, 0.17mmol) and sodium triacetoxyborohydride (99 mg, 0.47 mmol) was preparedN-butyl-3-[2-(butylamino)-4-pyrimidinyl]-2-[4-(dimethylamino)phenyl]pyrazolo[1,5-a]pyridin-7-amine(40.5 mg, 76%) as a pale yellow solid. ¹H NMR (CDCl₃): δ 7.80 (m, 2 H),7.50 (d, 2 H), 7.33 (t, 1 H), 6.79 (d, 2 H), 6.44 (d, 1 H), 6.10 (t, 1H), 6.03 (d, 1 H), 3.54 (q, 2 H), 3.38 (q, 2 H), 3.03 (s, 6 H),1.80–1.43 (m, 8 H), 0.99 (t, 6 H); MS m/z 458 (M+1).

EXAMPLE 242-(2-Bromophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine

a) 1-(2-Bromophenyl)-2-(6-chloro-2-pyridinyl)ethanone

In a similar manner as described in Example 1 from ethyl 2-bromobenzoate(50.0 g, 218 mmol) and 6-chloro-2-picoline (24 mL, 218 mmol),1-(2-bromophenyl)-2-(6-chloro-2-pyridinyl)ethanone (52.4 9, 77%) wasobtained as a yellow solid. ¹H NMR (CDCl₃): δ 7.53 (d, 1 H), 7.45 (d, 1H), 7.25 (d, 1 H), 7.05 (d, 1 H), 6.97 (d, 1 H), 6.67 (d, 1H), 6.53 (d,1H), 5.28 (s, 1H); MS m/z 310 (M+1).

b) 1-(2-Bromophenyl)-2-(6-chloro-2-pyridinyl)ethanone oxime

In a similar manner as described in Example 1 from1-(2-bromophenyl)-2-(-6-chloro-2-pyridinyl)ethanone (52.4 g, 169 mmol)was obtained 1-(2-bromophenyl)-2-(-6-chloro-2-pyridinyl)ethanone oxime(36.5 g, 66%) as a pale yellow solid. ¹H NMR (CDCl₃): δ 7.50–7.45 (m,2H), 7.23–7.07 (m, 6H), 4.29 (s, 2H); MS m/z 325 (M+1).

c) 2-(2-Bromophenyl)-7-chloropyrazolo[1,5-a]pyridine

In a similar manner as described in Example 1 from1-(2-bromophenyl)-2-(6-chloro-2-pyridinyl)ethanone oxime (36.5 g, 112mmol), 2-(2-bromophenyl)-7-chloropyrazolo[1,5-a]pyridine (21.0 g, 61%)was obtained as a yellow solid. ¹H NMR (CDCl₃): δ 7.83 (dd, 1H), 7.65(d, 1H), 7.51 (d, 1H), 7.37 (t, 1H), 7.21 (m, 1H), 7.07 (m, 2H), 6.89(d, 1H); MS m/z 307 (M+1).

d) 1-[2-(2-Bromophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]ethanone

In a similar manner as described in Example 1 from2-(2-bromophenyl)-7-chloropyrazolo[1,5-a]pyridine (21.0 g, 68.3 mmol),1-[2-(2-bromophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]ethanone (15.7g, 66%) was obtained as orange needles. ¹H NMR (CDCl₃): δ 8.48 (dd, 1H),7.72 (d, 1H), 7.49–7.36 (m, 4H), 7.18 (dd, 1H), 2.06 (s, 3H); MS m/z 349(M+1).

e)1-[2-(2-Bromophenyl)-7-(cyclopentylamino)pyrazolo[1,5-a]pyridin-3-yl]ethanone

In a similar manner as described in Example 1 from1-[2-(2-bromophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]ethanone (3.00g, 8.6 mmol),1-[2-(2-bromophenyl)-7-(cyclopentylamino)pyrazolo[1,5-a]pyridin-3-yl]ethanone(0.93 g, 27%) was obtained as a yellow syrup. ¹H NMR (CDCl₃): δ7.73–7.68 (m, 2H), 7.43 (m, 3H), 7.35–7.31 (m, 1H), 6.12 (d, 1H), 5.98(d, 1 H), 3.95 (m, 1 H), 2.08 (m, 2), 1.98 (s, 3H), 1.76–1.53 (m, 6H);MS m/z 398 (M+1).

f)(2E)-1-[2-(2-Bromophenyl)-7-(cyclopentylamino)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one

In a similar manner as described in Example 1 from1-[2-(2-bromophenyl)-7-(cyclopentylamino)pyrazolo[1,5-a]pyridin-3-yl]ethanone(0.93 g, 2.3 mmol),(2E)-1-[2-(2-bromophenyl)-7-(cyclopentylamino)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one(0.57 g, 54%) was obtained as a brown syrup. ¹H NMR (CDCl₃): δ 7.78 (d,1H), 7.66 (d, 1H), 7.53 (d, 1H), 7.46 (m, 1H), 7.39 (t, 1H), 7.31–7.22(m, 2H), 6.02 (d, 1H), 5.85 (d, 1H), 4.80 (d, 1H), 3.95 (m, 1 H), 2.90(broad s, 3H), 2.30 (broad s, 3H), 2.08 (m, 2H), 1.77–1.63 (m, 6H); MSm/z 455 (M+1).

g)2-(2-Bromophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-pyrazolo[1,5-a]pyridin-7-amine

In a similar manner as described in Example 1 from(2E)-1-[2-(2-bromophenyl)-7-(cyclopentylamino)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one(200 mg, 0.46 mmol),2-(2-bromophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine(110 mg, 48%) was obtained as a yellow foam. ¹H NMR (CDCl₃): δ 7.90 (m,2H), 7.66 (d, 1H), 7.44 (m, 1H), 7.39 (t, 1H), 7.32–7.27 (m, 2H),6.04–5.96 (m, 3H), 5.02 (m, 1H), 4.21 (m, 1H), 3.95 (m, 1H), 2.10–1.96(m, 4H), 1.75–1.43 (m, 12H); MS m/z 517 (M+1).

EXAMPLE 252-(3-Bromophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine

a) 1-(3-Bromophenyl)-2-(6-chloro-2-pyridinyl)ethanone

In a similar manner as described in Example 1 from ethyl 3-bromobenzoate(50.6 g, 220 mmol) and 6-chloro-2-picoline (24 mL, 220 mmol),1-(3-bromophenyl)-2-(6-chloro-2-pyridinyl)ethanone (59.4 g, 87%) wasobtained as a yellow solid. ¹H NMR (CDCl₃): δ 7.96 (broad s, 1H), 7.71(d, 1H), 7.35–7.25 (m, 3H), 6.98 (t, 1H), 6.81 (d, 1H), 6.58 (d, 1H),5.84 (s, 1H); MS m/z 310 (M+1).

b) 1-(3-Bromophenyl)-2-(6-chloro-2-pyridinyl)ethanone oxime

In a similar manner as described in Example 1, from1-(3-bromophenyl)-2-(6-chloro-2-pyridinyl)ethanone (59.1 g, 190 mmol)the 1-(3-bromophenyl)-2-(6-chloro-2-pyridinyl)ethanone oxime (58.3 g,94%) was obtained as a white solid. ¹H NMR (CDCl₃): δ 7.96 (s, 1H),7.67–7.50 (m, 3H), 7.28–7.18 (m, 3H), 4.80 (b, 1H), 4.39 (s, 2H); MS m/z325 (M+1).

c) 2-(3-Bromophenyl)-7-chloropyrazolo[1,5-a]pyridine

In a similar manner as described in Example 1 from1-(3-bromophenyl)-2-(6-chloro-2-pyridinyl)ethanone oxime (59.1 g, 181.5mmol), 2-(3-bromophenyl)-7-chloropyrazolo[1,5-a]pyridine (24.5 g, 44%)was obtained as a yellow solid. ¹H NMR (CDCl₃): δ 8.13 (dd, 1H), 7.90(d, 1H), 7.47 (m, 2H), 7.29 (t, 1H), 7.05 (t, 1H), 6.88 (m, 2H); MS m/z307 (M+1).

d) 1-[2-(3-Bromophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]ethanone

In a similar manner as described in Example 1 from2-(3-bromophenyl)-7-chloropyrazolo[1,5-a]pyridine (16.5 g, 53.6 mmol),1-[2-(3-bromophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]ethanone (8.6g, 46%) was obtained as pinkish needles. ¹H NMR (CDCl₃): δ 8.46 (d, 1H),7.83 (s, 1H), 7.69 (d, 1H), 7.59–7.40 (m, 3H), 7.22 (d, 1H), 2.21 (s,3H); MS m/z 349 (M+1).

e)1-[2-(3-Bromophenyl)-7-(cyclopentylamino)pyrazolo[1,5-a]pyridin-3-yl]ethanone

In a similar manner as described in Example 1 from1-[2-(3-bromophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]ethanone (3.00g, 8.6 mmol),1-[2-(3-bromophenyl)-7-(cyclopentylamino)pyrazolo[1,5-a]pyridin-3-yl]ethanone(1.90 g, 56%) was obtained as a yellow syrup. ¹H NMR (CDCl₃): δ 7.74(dd,1 H), 7.61–7.57 (m, 2H), 7.50 (d, 1H), 7.41 (t, 1H), 7.32 (t, 1H),6.10 (dd, 1H), 5.99 (d, 1H), 3.95 (m, 1H), 2.12–2.05 (m, 5H), 1.78–1.63(m, 6H); MS m/z 398 (M+1).

f)(2E)-1-[2-(3-Bromophenyl)-7-(cyclopentylamino)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one

In a similar manner as described in Example 1 from1-[2-(3-bromophenyl)-7-(cyclopentylamino)pyrazolo[1,5-a]pyridin-3-yl]ethanone(1.90 g, 4.8 mmol),(2E)-1-[2-(3-bromophenyl)-7-(cyclopentylamino)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one(1.87 g, 86%) was obtained as a brown syrup. ¹H NMR (CDCl₃): δ 7.88 (s,1H) 7.64–7.49 (m, 4H), 7.30–7.24 (m, 2H), 6.00 (d, 1H), 5.93 (d, 1H),5.03 (d, 1H), 3.95 (m, 1H), 3.10–2.35 (b, 6H), 2.10–2.06 (m, 2H),1.77–1.62 (m, 6H); MS m/z 455 (M+1).

g)2-(3-Bromophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-pyrazolo[1,5-a]pyridin-7-amine

In a similar manner as described in Example 1 from(2E)-1-[2-(3-bromophenyl)-7-(cyclopentylamino)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one(500 mg, 1.1 mmol),2-(3-bromophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine(500 mg, 88%) was obtained as a yellow solid. ¹H NMR (CDCl₃): δ 8.00 (d,1H), 7.83 (s, 1H), 7.65 (d, 1H), 7.51 (m, 2H), 7.29–7.22 (m, 2H), 6.28(d, 1H), 6.00 (d, 1H), 5.96 (d, 1H), 5.00 (d, 1H), 4.27 (m, 1H), 3.97(m, 1H), 2.11–2.00 (m, 4H), 1.79–1.46 (m, 12H); MS m/z 517 (M+1).

EXAMPLE 264-[2-(3-Bromophenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine

a)1-[2-(3-Bromophenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone

In a similar manner as described in Example 1 from1-[2-(3-bromophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]ethanone (3.00g, 8.6 mmol) and pyrrolidine,1-[2-(3-bromophenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone(3.18 g, 96%) was obtained as a yellow syrup. ¹H NMR (CDCl₃): δ7.78–7.74 (m, 2H), 7.56 (d, 1H), 7.50 (d, 1H), 7.38–7.28 (m, 2H), 6.14(d, 1H), 3.72 (m, 4H), 2.12 (s, 3H), 1.98 (m, 4H); MS m/z 384 (M+1).

b)(2E)-1-[2-(3-Bromophenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one

In a similar manner as described in Example 1 from1-[2-(3-bromophenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone(3.1 g, 8.1 mmol),(2E)-1-[2-(3-bromophenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one(2.15 g, 61%) was obtained as a brown syrup. ¹H NMR (CDCl₃): δ 7.90 (dd,1H), 7.76 (d, 1H), 7.66 (d, 1H), 7.54 (d, 1H), 7.51 (d, 1H), 7.26–7.20(m, 2H), 6.06 (d, 1H), 5.07 (d, 1H), 3.70 (m, 4H), 2.90 (b, 3H), 2.50(b, 3H), 1.99 (m, 4H); MS m/z 4.39 (M+1).

c)4-[2-(3-Bromophenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopenyl-2-pyrimidinamine

In a similar manner as described in Example 1 from(2E)-1-[2-(3-bromophenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one(500 mg, 1.1 mmol),4-[2-(3-bromophenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(451 mg, 79%) was obtained as a yellow solid. ¹H NMR (d₆-DMSO): δ 8.00(d, 1H), 7.71 (s, 1H), 7.60 (d, 1H), 7.54 (d, 1H), 7.37 (t, 1H), 7.29(t, 1H), 6.98 (d, 1H), 6.18 (d, 2H), 4.02 (m, 1H), 3.66 (m, 4H), 1.90(m, 4H), 1.80–1.44 (m, 8H); MS m/z 503 (M+1); Anal. Calcd. forC₂₆H₂₇N₆Br: C, 62.03; H, 5.41; N, 16.69. Found: C, 61.88; H. 5.40; N,16.40.

EXAMPLE 27N-[3-(2-Amino-4-pyrimidinyl)-2-(3-bromophenyl)pyrazolo[1,5-a]pyridin-7-yl]-N-cyclopentylamine

In a similar manner as described in Example 1 from(2E)-1-[2-(3-bromophenyl)-7-(cyclopentylamino)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one(500 mg, 1.1 mmol) and guanidine sulfate (358 mg, 1.65 mmol),N-[3-(2-amino-4-pyrimidinyl)-2-(3-bromophenyl)pyrazolo[1,5-a]pyridin-7-yl]-N-cyclopentylamine(380 mg, 77%) was obtained as a yellow solid. ¹H NMR (CDCl₃): δ 8.01 (d,1H), 7.84 (s, 1H), 7.64 (d, 1H), 7.54–7.49 (m, 2H), 7.30–7.22 (m, 2H),6.36 (d, 1H), 6.01 (d, 1H), 5.97 (d, 1H), 4.95 (broad s, 2H), 3.97 (m,1H), 2.12 (m, 2H), 1.79–1.57 (m, 6H); MS m/z 448 (M+1); Anal. Calcd. forC₂₂H₂₁N₆Br: C, 58.80; H, 4.71; N,18.70. Found: C, 58.61; H, 4.75; N,18.58.

EXAMPLE 284-[2-(3-Bromophenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

In a similar manner as described in Example 1 from(2E)-1-[2-(3-bromophenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one(500 mg, 1.1 mmol) and guanidine sulfate,4-[2-(3-bromophenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(300 mg, 61%) was obtained as a yellow solid. ¹H NMR (d₆-DMSO): δ 8.03(d, 1H), 7.87 (d, 1H), 7.81 (s, 1H), 7.70–7.62 (m, 2H), 7.46 (t, 1H),7.35 (t, 1H), 6.58 (broad s, 2H), 6.26 (d, 1H), 6.22 (d, 1H), 3.75 (m,4H), 1.98 (m, 4H); MS m/z 435 (M+1); Anal. Caled. for C₂₁H₁₉N₆Br: C,57.94; H, 4.40; N. 19.31. Found: C, 57.91; H, 4.51; N, 19.07.

EXAMPLE 292-[1,1′-Biphenyl]-3-yl-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine

To a solution of2-(3-bromophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine(100 mg, 0.19 mmol) in dimethylformamide (6 mL) was added phenylboronicacid (47 mg, 0.39 mmol), palladium (II) acetate (4.3 mg, 0.02 mmol),potassium carbonate (54 mg, 0.39 mmol) and triphenyl phosphine (30 mg,0.08 mmol). The reaction was heated at 100° C. for 24 hours. Afterallowing the reaction mixture to cool to room temperature, ethyl acetateand water were added. The organic layer was separated and washed withwater, then brine and dried (magnesium sulfate). Filtration andconcentration, followed by purification with flash chromatography (4:6ethyl acetate:hexanes) gave2-[1,1′-biphenyl]-3-yl-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amineas a yellow foam (87 mg, 89%). ¹H NMR (CDCl₃): δ 8.01 (d, 1H), 7.92 (s,1H), 7.81 (d, 1H), 7.69–7.62 (m, 4H), 7.53 (t, 1H), 7.47–7.43 (m, 2H),7.38–7.32 (m, 2H), 6.40 (d, 1H), 6.09–6.05 (m, 2H), 5.16 (m, 1H), 4.37(m, 1H), 4.03 (m, 1H), 2.15–2.06 (m, 4H), 1.82–1.64 (m, 12H); MS m/z 515(M+1).

EXAMPLE 304-[2-[1,1′-Biphenyl]-3-yl-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine

In a similar manner as described in Example 29 from4-[2-(3-bromophenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(100 mg, 0.20 mmol),4-[2-[1,1′-biphenyl]-3-yl-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(70 mg, 70%) was obtained as a yellow foam. ¹H NMR (CDCl₃): δ 8.04 (d,1H), 7.93 (s, 1H), 7.92 (m, 1H), 7.67–7.59 (m, 4H), 7.52–7.42 (m, 3H),7.36 (t, 1H), 7.29–7.24 (m, 1H), 6.44 (d, 1H), 6.11 (d, 1H), 5.05 (d,1H), 4.37 (m, 1H), 3.78 (m, 4H), 2.09–2.02 (m, 6H), 1.76–1.54 (m, 6H);MS m/z 501 (M+1).

EXAMPLE 31N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[3-(4-pyridinyl)phenyl]pyrazolo[1,5-a]pyridin-7-amine

In a similar manner as described in Example 29 from2-(3-bromophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine(100 mg, 0.19 mmol) and pyridine-4-boronic acid,N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[3-(4-pyridinyl)phenyl]pyrazolo[1,5-a]pyridin-7-amine(41 mg, 42%) was obtained as a yellow foam. ¹H NMR (CDCl₃): δ 8.66 (d,2H), 8.02 (d, 1H), 7.96 (s, 1H), 7.76–7.69 (m, 3H), 7.58–7.51 (m, 3H),7.33 (t, 1H), 6.36 (d, 1H), 6.06–6.04 (m, 2H), 5.15 (m, 1H), 4.32 (m,1H), 4.01 (m, 1H), 2.17–2.03 (m, 4H), 1.81–1.52 (m, 12H); MS m/z 516(M+1).

EXAMPLE 32N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[3-(3-thienyl)phenyl]pyrazolo[1,5-a]pyridin-7-amine

In a similar manner as described in Example 29 from2-(3-bromophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine(200 mg, 0.39mmol) and thiophene-3-boronic acid,N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[3-(3-thienyl)phenyl]pyrazolo[1,5-a]pyridin-7-amine(94 mg, 47%) was obtained as a yellow foam. ¹H NMR (CDCl₃): δ 8.00 (d,1H), 7.92 (s. 1H), 7.81 (d, 1H), 7.67 (d, 1H), 7.57 (d, 1H), 7.49–7.42(m, 2H), 7.40–7.34 (m, 2H), 7.32–7.27 (m, 1H), 6.38 (d, 1H), 6.09–6.03(m, 2H), 5.22 (d, 1H), 4.36 (m, 1H), 4.00 (m, 1H), 2.15–2.05 (m, 4H),1.82–1.56 (m, 12H); MS m/z 521 (M+1).

EXAMPLE 33N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[3-(2-thienyl)-phenyl]pyrazolo[1,5-a]pyridin-7-amine

In a similar manner as described in Example 29 from2-(3-bromophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine(200 mg, 0.39 mmol) and thiophene-2-boronic acid,N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[3-(2-thienyl)phenyl]pyrazolo[1,5-a]pyridin-7-amine(84 mg, 42%) was obtained as a yellow foam. ¹H NMR (CDCl₃): δ 8.00 (d,1H), 7.95 (s,1H), 7.79 (d, 1H), 7.69 (d, 1H), 7.56 (d, 1H), 7.45 (t,1H), 7.34–7.27 (m, 3H), 7.09 (m, 1H), 6.39 (d, 1H), 6.17 (m, 2H), 5.16(m, 1H), 4.35 (m, 1H), 4.01 (m, 1H), 2.16 (m, 4H), 1.82–1.56 (m, 12H);MS m/z 521 (M+1). U16951-72

EXAMPLE 342-(3-Aminophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine

a)N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-{3-[(diphenylmethylene)amino]phenyl}pyrazolo[1,5-a]pyridin-7-amine

To a solution of2-(3-bromophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine(3.00 g, 5.8 mmol) in toluene (60 mL) was added benzophenone imine (3.15g, 17.4 mmol), tris(dibenzylideneacetone)dipalladium (0.26 g, 0.3 mmol),rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.54 g, 0.15 mmol) andsodium tert-butoxide (1.67 g, 17.4 mmol). The reaction was heated atreflux for 5 hours, then allowed to cool to room temperature. Water andethyl acetate were added to the reaction mixture. The phases wereseparated and the organic phase was washed with brine and dried(magnesium sulfate). Filtration and concentration of the filtratefollowed by purification with flash chromatography (4:6 ethylacetate:hexanes) gaveN-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-{3-[(diphenylmethylene)amino]phenyl}-pyrazolo[1,5-a]pyridin-7-amine(2.61 g, 73%) as a yellow solid. ¹H NMR (CDCl₃): δ 7.89 (d, 1H),7.80–7.75 (m, 3H), 7.48 (m, 1H), 7.41 (m, 2H), 7.27 (m, 5H), 7.23–7.12(m, 4H), 7.04 (s, 1H), 6.80 (d, 1H), 6.03–5.97 (m, 3H), 4.39 (m, 1H),4.00 (m, 1H), 2.15–2.05 (m, 4H), 1.83–1.56 (m, 12H); MS m/z 618 (M+1).

b)2-(3-Aminophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine

To a solution ofN-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-{3-[(diphenylmethylene)amino]phenyl}-pyrazolo[1,5-a]pyridin-7-amine(2.61 g, 4.22 mmol) in tetrahydrofuran (30 mL) at 0° C. was added 4Nhydrochloric acid (20 mL) dropwise. Subsequently, the reaction mixturewas stirred for 5 minutes. The reaction mixture was diluted with ether,then saturated aqueous bicarbonate was added slowly till the ether layerturned clear. The resulting mixture was stirred for 30 minutes. Thephases were separated, the organic phase was washed with water, brineand dried (magnesium sulfate). Filtration and concentration of thefiltrate to a solid, followed by recrystallization from ethylacetate-hexanes, gave2-(3-aminophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine(1.78 g, 93%) as a pale yellow solid. ¹H NMR (CDCl₃): δ 7.92 (d, 1H),7.82 (d, 1H), 7.32 (t, 1H), 7.22 (m, 2H), 7.00–6.94 (m, 2H), 6.78 (m,1H), 6.34 (d, 1H), 6.04 (m, 2H), 4.38 (m, 1H), 4.00 (m, 1H), 3.75(broad, 2H), 2.14–2.05 (m, 4H), 1.83–1.54 (m, 12H); MS m/z 454 (M+1).

EXAMPLE 35N-(3-{7-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenyl)acetamide

To a suspension of2-(3-aminophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine(150 mg, 0.33 mmol) in dimethylformamide (10 mL) was added triethylamine(51 δL, 0.36 mmol). The reaction mixture was cooled to 0° C. and flushedwith nitrogen, then acetyl chloride (26 μL, 0.36 mmol) was addeddropwise. The reaction mixture was stirred at room temperatureovernight. Water was added and the resulting mixture was extracted withethyl acetate. The ethyl acetate phase was dried (magnesium sulfate),filtered and concentrated to a solid. This solid was purified by flashchromatography (95:5 chloroform:methanol) to giveN-(3-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenyl)acetamide(151 mg, 92%) as a tan solid. ¹H NMR (CDCl₃): δ 8.19 (s, 1H), 7.95 (d,1H), 7.82 (d, 1H), 7.75 (d, 1H), 7.63 (s, 1H), 7.36–7.25 (m, 3H), 6.28(d, 1H), 6.00 (m, 2H), 5.17 (d, 1H), 4.32 (m, 1H), 3.96 (m, 1H), 2.11(s, 3H), 2.11–2.02 (m, 4H), 1.76–1.48 (m, 12H); MS m/z 496 (M+1).

EXAMPLE 36N-(3-{7-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]-pyrazolo[1,5-a]pyridin-2-yl}phenyl)methanesulfonamide

To a suspension of2-(3-aminophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine(150, mg, 0.33 mmol) in N,N-dimethylformamide (5 mL) was added pyridine(40 μL, 0.49 mmol). The reaction mixture was cooled to 0° C. undernitrogen, then methanesulfonyl chloride (28 μL, 0.36 mmol) was addeddropwise. After stirring at room temperature for 18 hours, the reactionmixture turned clear. Ethyl acetate and water were added and the phasesseparated. The organic phase was washed with water and brine, then driedover magnesium sulfate. Filtration and concentration, followed by flashchromatography (95:5 chloroform:methanol) gaveN-(3-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenyl)methanesulfonamide(170 mg, 96%) as a yellow syrup. ¹H NMR (CDCl₃): δ 7.93 (d, 1H), 7.66(d, 1H), 7.42 (m, 1H), 7.35–7.25 (m, 5H), 6.25 (m, 1H), 5.99 (m, 2H),5.62 (broad, 1H), 4.29 (m, 1H), 3.96 (m, 1H), 2.94 (s, 3H), 2.10–1.99(m, 4H), 1.77–1.49 (m, 12H). MS m/z 532 (M+1).

EXAMPLE 374-[2-(3-Aminophenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cylopentyl-2-pyrimidinamine

a)N-Cyclopentyl-4-{2-[3-[(diphenylmethylene)amino]phenyl]-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl}-2-pyrimidinamine

In a similar manner as described in Example 16 from4-[2-(3-bromophenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(200 mg, 0.40 mmol),N-cyclopentyl-4-{2-[3-[(diphenylmethylene)amino]phenyl]-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl}-2-pyrimidinamine(156 mg, 65%) was obtained as a yellow solid. ¹H NMR (CDCl₃): δ 7.90 (m,2H), 7.72–7.70 (m, 2H), 7.43–7.35 (m, 3H), 7.23–7.16 (m, 4H), 7.13–7.11(m, 4H), 7.05 (s, 1H), 6.70 (m, 1H), 6.02 (m, 2H), 4.98 (d, 1H), 4.33(m, 1H), 3.68 (m, 4H), 2.07 (m, 2H), 1.99 (m, 4H), 1.72–1.50 (m, 6H); MSm/z 604 (M+1).

b)4-[2-(3-Aminophenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine

In a similar manner as described in Example 16 fromN-cyclopentyl-4-{2-[3-[(diphenylmethylene)amino]phenyl]-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl}-2-pyrimidinamine(150 mg, 0.25 mmol),4-[2-(3-aminophenyl)-7-(1-pyrrolidinyl)-pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(104 mg, 95%) was obtained as a yellow foam. ¹H NMR (CDCl₃): δ 7.97 (d,1H), 7.92 (d, 1H), 7.21–7.15 (m, 2H), 7.01 (d, 1H), 6.69 (s, 1H), 6.91(dd, 1H), 6.38 (d, 1H), 6.05 (d, 1H), 5.29 (m, 1H), 4.37 (m, 1H), 3.72(m, 4H), 3.70 (broad, 2H), 2.07 (m, 2H), 1.98 (m, 4H), 1.74–1.53 (m,6H); MS m/z 440 (M+1).

EXAMPLE 38N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-phenylpyrazolo-[1,5-a]pyridin-7-amine

To a solution of2-(3-bromophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine(100 mg, 0.19 mmol) in toluene (10 mL) was added tributyltin hydride(112 mg, 0.39 mmol) and 2,2′-azobisisobutyronitrile (9.4 mg, 0.057mmol). After heating at reflux for 4 hours, the reaction mixture wasallowed to cool to room temperature. Concentration, followed bypurification with flash chromatography (40:60 ethyl acetate:hexanes)gaveN-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-phenylpyrazolo[1,5-a]pyridin-7-amineas a yellow foam (39 mg, 46%). ¹H NMR (CDCl₃): δ 7.98 (d, 1H), 7.78 (d,1H), 7.64 (m, 2H), 7.45 (m, 2H), 7.33–7.26 (m, 2H), 6.27 (d, 1H), 6.04(m, 2H), 5.12 (d, 1H), 4.35 (m, 1H), 4.00 (m, 1H), 2.09–2.03 (m, 4H),1.81–1.59 (m, 12H). MS m/z 439 (M+1).

EXAMPLE 393-{7-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}benzonitrile

To a solution of2-(3-bromophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine(500 mg, 0.97 mmol) in N,N-dimethylformamide (25 mL) was added zinccyanide (68 mg, 0.58 mmol), tris(dibenzylidineacetone)bipalladium(0)(888 mg, 0.97 mmol) and 1,1′-bis(diphenylphosphino) ferrocene (1.29 g,2.3 mmol). The resultant mixture was heated at 120° C. for 20 hours.After cooling to room temperature, ethyl acetate was added to thereaction mixture. The organic phase was washed with water, brine anddried over magnesium sulfate. Filtration and concentration, followed bypurification with flash chromatography (40:60 ethyl acetate:hexanes)gave3-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}benzonitrile(0.19 g, yield 42%) as a yellow foam. ¹H NMR (CDCl₃): δ 8.07 (m, 2H),7.89 (d, 1H), 7.70 (d, 1H), 7.62 (d, 1H), 7.52 (t, 1H), 7.33 (t, 1H),6.33 (d, 1H), 6.06 (d, 1H), 6.00 (d, 1H), 5.16 (d, 1H), 4.25 (m, 1H),4.02 (m, 1H), 2.15 (m, 2H), 2.03 (m, 2H), 1.85–1.51 (m, 12H). MS m/z 464(M+1).

EXAMPLE 403-{7-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]-pyrazolo[1,5-a]pyridin-2-yl}benzamide

3-{7-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}benzonitrile(45 mg, 0.097 mmol) was dissolved in hot methanol (2 mL). Subsequently,the solution was cooled down to room temperature and 30% ammoniumhydroxide (2 mL) was added. The reaction mixture was then cooled to 0°C., and 30% hydrogen peroxide was added. After stirring at roomtemperature for 8 hours, water was added and the resulting mixtureextracted with ethyl acetate. The organics were dried over magnesiumsulfate. Filtration and concentration, followed by purification withflash chromatography (95:5 dichloromethane:methanol), gave3-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}benzamide(18 mg, 39% yield) as a yellow solid. ¹H NMR (CDCl₃): δ 8.12 (s, 1H),7.99 (d, 1H), 7.92 (d, 1H), 7.79 (d, 1H), 7.70 (d, 1H), 7.51 (t, 1H),7.32 (t, 1H), 6.28 (d, 1H), 6.18 (broad, 1H), 6.05 (d, 1H), 6.02 (d,1H), 5.82 (broad, 1H), 5.25 (d, 1H), 4.30 (m, 1H), 4.00 (m, 1H), 2.15(m, 2H), 2.03 (m, 2H), 1.81–1.50 (m, 12H). MS m/z 482 (M+1).

EXAMPLE 413-{7-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo-[1,5-a]pyridin-2-yl}benzoicacid

To a solution of3-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}benzonitrile(50 mg, 0.1 mmol) in methanol was added 4N potassium hydroxide. Afterheating at 85° C. for 2 days, the reaction mixture was cooled to roomtemperature and acidified with 2N hydrochloric acid. The solution wasextracted with ethyl acetate. The organic phases were combined and driedover magnesium sulfate. Filtration and concentration, followed bypurification by flash chromatography (90:10 ethyl acetate:methanol) gave3-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}benzoicacid (10 mg, 19%) as a brown foam. ¹H NMR (CDCl₃): δ 8.11 (s, 1H), 8.00(d, 1H), 7.96 (d, 1H), 7.80 (broad s, 1H), 7.64 (d, 1H), 7.46 (t, 1H),7.37 (t, 1H), 6.98 (d, 1H), 6.57 (d, 1H), 6.21 (d, 1H), 6.11 (broad,1H), 4.12 (m, 1H), 4.01 (m, 1H), 2.06 (m, 2H), 1.88 (m, 2H), 1.69–1.49(m, 12H). MS m/z 483 (M+1); 481 (M−1).

EXAMPLE 42N-{4-[2-(3-Bromo-4-methoxyphenyl)-7-(cyclopentylamino)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-cyclopentylamine

a) 1-(3-Bromo-4-methoxyphenyl)-2-(6-chloro-2-pyridinyl)ethanone

In a similar manner as described in Example 1 from ethyl3-bromo-4-methoxybenzoate (13.6 g, 52.5 mmol) and 6-chloro-2-picoline(5.7 mL, 52.5 mmol),1-(3-bromo-4-methoxyphenyl)-2-(6-chloro-2-pyridinyl)ethanone (15.8 g,88%) was obtained as a yellow solid (existing as a mixture of ketone andenol tautomers). ¹H NMR (CDCl₃) of the ketone: δ 8.27 (s, 1H), 8.02 (dd,1H), 7.63 (t, 1H), 7.23 (m, 2H), 6.94 (d, 1H), 4.41 (s, 2H), 3.97 (s,3H); MS m/z340 (M+1).

b) 1-(3-Bromo-4-methoxyphenyl)-2-(6-chloro-2-pyridinyl)ethanone oxime

In a similar manner as described in Example 1 from1-(3-bromo-4-methoxyphenyl)-2-(6-chloro-2-pyridinyl)ethanone (15.8 g,49.3 mmol) was obtained1-(3-bromo-4-methoxyphenyl)-2-(6-chloro-2-pyridinyl)ethanone oxime (12.6g, 76%) as a white solid. ¹H NMR (CDCl₃): δ 8.00 (d, 1H), 7.63 (dd, 1H),7.54 (t, 1H), 7.19–7–7.15 (m, 2H), 6.86 (d, 1H), 4.34 (s, 2H), 3.90 (s,3H); MS m/z 357 (M+1).

c) 2-(3-Bromo-4-methoxyphenyl)-7-chloropyrazolo[1,5-a]pyridine

To a solution of1-(3-bromo-4-methoxyphenyl)-2-(6-chloro-2-pyridinyl)ethanone oxime (1.00g, 2.8 mmol) in dimethoxyethane (30 mL) at 0° C. was added slowlymethylsulfonyl chloride (0.24 mL, 3.08 mmol). The reaction was stirredfor 15 minutes and then triethylamine (1.7 mL, 12.3 mmol) indimethoxyethane (3 mL) was added to the reaction. Upon addition of thetriethylamine a precipitate formed. Once the addition of thetriethylamine solution had been completed the reaction mixture wasallowed to warm to room temperature and was stirred for 1 hour. Theprecipitate was removed by filteration and the precipitate was washedwith dimethoxyethane. To the combined filtrate was added iron (II)chloride (14 mg, 0.12 mmol) and the resulting mixture was heated at 80°C. for 15 hours. The reaction mixture was allowed to cool to roomtemperature. Ethyl acetate was added to dilute the mixture and theorganic phase was washed with water, brine and dried (magnesiumsulfate). Filtration and concentration of the filtrate, followed byflash chromatography (4:6 ethyl acetate:hexanes) gave2-(3-bromo-4-methoxyphenyl)-7-chloropyrazolo[1,5-a]pyridine (86 mg, 9%).¹H NMR (CDCl₃): δ 8.21 (d, 1H), 7.95 (d, 1H), 7.48 (d, 1H), 7.10 (t,1H), 6.98 (d, 1H), 6.88 (d, 1H), 6.84 (s, 1H), 3.96 (s, 3H); MS m/z 337(M+1).

d)1-[2-(3-Bromo-4-methoxyphenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]ethanone

In a similar manner as described in Example 1 from2-(3-bromo-4-methoxyphenyl)-7-chloropyrazolo[1,5-a]pyridine (0.62 g,1.83 mmol),1-[2-(3-bromo-4-methoxyphenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]ethanone(0.45 g, 65%) was obtained as a pink solid. ¹H NMR (CDCl₃): δ 8.40 (m,1H), 7.84 (s, 1H), 7.54 (dd, 1H), 7.46 (m, 1H), 7.16 (m, 1H), 7.03 (d,1H), 3.99. (s, 3H), 2.20 (s, 3H); MS m/z 379 (M+1).

e)1-[2-(3-Bromo-4-methoxyphenyl)-7-(cyclopentylamino)pyrazolo[1,5-a]pyridin-3-yl]ethanone

In a similar manner as described in Example 1 from1-[2-(3-bromo-4-methoxyphenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]ethanone(0.51 g, 1.3 mmol),1-[2-(3-bromo-4-methoxyphenyl)-7-(cyclopentylamino)pyrazolo[1,5-a]pyridin-3-yl]ethanone(0.24 g, 42%) was obtained as a yellow foam. ¹H NMR (CDCl₃): δ 7.84 (d,1H), 7.65 (d, 1H), 7.54 (dd, 1H), 7.44 (t, 1H), 7.02 (d, 1H), 6.15 (d,1H), 6.04 (d, 1H), 3.98 (m, 4H), 2.19 (s, 3H), 2.13 (m, 2H), 1.82–1.64(m, 6H); MS m/z 428 (M+1).

f)(2E)-1-[2-(3-Bromo-4-methoxyphenyl)-7-(cyclopentylamino)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one

In a similar manner as described in Example 1 from1-[2-(3-bromo-4-methoxyphenyl)-7-(cyclopentylamino)pyrazolo[1,5-a]pyridin-3-yl]ethanone(0.24 g, 0.56 mmol),(2E)-1-[2-(3-bromo-4-methoxyphenyl)-7-(cyclopentylamino)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one(0.13 g, 48%) was obtained as a brown syrup. ¹H NMR (CDCl₃): δ 7.96 (d,1H), 7.64 (m, 1H), 7.60–7.56 (m, 2H), 7.27 (t, 1H), 6.94 (d, 1H),6.00–5.98 (m, 2H), 5.13 (d, 1H), 3.94 (m, 1H), 3.91 (s, 3 H), 0.92 (b,3H), 2.55 (b, 3H), 2.08 (m, 2H), 1.78–1.64 (m, 6H); MS m/z 483 (M+1).

g)N-{4-[2-(3-Bromo-4-methoxyphenyl)-7-(cyclopentylamino)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-cyclopentylamine

In a similar manner as described in Example 1 from(2E)-1-[2-(3-bromo-4-methoxyphenyl)-7-(cyclopentylamino)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one(130 mg, 0.27 mmol),N-{4-[2-(3-bromo-4-methoxyphenyl)-7-(cyclopentylamino)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl)}-N-cyclopentylamine(84 mg, 57%) was obtained as a yellow solid. ¹H NMR (CDCl₃): δ 8.03 (d,1H), 7.93 (d, 1H), 7.71 (d, 1H), 7.54 (d, 1H), 7.30(t, 1H), 6.95 (d,1H), 6.36 (d, 1H), 6.04–6.00 (m, 2H), 5.12 (d, 1H), 4.34 (m, 1H), 4.00(m, 1H), 3.96 (s, 3H), 2.15–2.05 (m, 4H), 1.83–1.53 (m, 12H); MS m/z 547(M+1).

EXAMPLE 432-(3-Bromo-4-chlorophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine

a) 1-(3-Bromo-4-chlorophenyl)-2-(6-chloro-2-pyridinyl)ethanone

In a similar manner as described in Example 1 from ethyl3-bromo-4-chlorobenzoate (42.6 g, 171 mmol) and 6-chloro-2-picoline(18.7 mL, 171 mmol),1-(3-bromo-4-chlorophenyl)-2-(-6-chloro-2-pyridinyl)ethanone wasobtained as a pale yellow solid existing as a mixture of ketone and enoltautomers. ¹H NMR (CDCl₃) of ketone: δ 8.30 (d, 1H), 7.92 (dd, 1H),7.69–7.54 (m, 2H), 7.24 (m, 2H), 4.42 (s, 2H); MS m/z 344 (M+1).

b) 1-(3-Bromo-4-chlorophenyl)-2-(6-chloro-2-pyridinyl)ethanone oxime

In a similar manner as described in Example 1 from1-(3-bromo-4-chlorophenyl)-2-(6-chloro-2-pyridinyl)ethanone was obtained1-(3-bromo-4-chlorophenyl)-2-(6-chloro-2-pyridinyl)ethanone oxime (22.0g, yield 36% for the two steps) as a white solid. ¹H NMR (CDCl₃): δ 8.20(b, 1H), 8.06 (d, 1H), 7.62–7.53 (m, 2H), 7.42 (d, 1H), 7.18–7.14 (m,2H), 4.32 (s, 2H); MS m/z 359 (M+1).

c) 2-(3-Bromo-4-chlorophenyl)-7-chloropyrazolo[1,5-a]pyridine

In a similar manner as described in Example 1 from1-(3-bromo-4-chlorophenyl)-2-(6-chloro-2-pyridinyl)ethanone oxime (17.57g, 48.8 mmol) was obtained2-(3-bromo-4-chlorophenyl)-7-chloropyrazolo[1,5-a]pyridine (13.7 g,82%). ¹H NMR (CDCl₃): δ 8.28 (d, 1H), 7.99 (dd, 1H), 7.52 (m, 2H), 7.10(t, 1H), 6.94–6.90 (m, 2H); MS m/z 341 (M+1).

d)1-[2-(3-Bromo-4-chlorophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]ethanone

In a similar manner as described in Example 1 from2-(3-bromo-4-chlorophenyl)-7-chloropyrazolo[1,5-a]pyridine (13.9 g, 40.8mmol),1-[2-(3-bromo-4-chlorophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]ethanone(12.5 g, 80%) was obtained as a tan solid. ¹H NMR (CDCl₃): δ 8.40 (d,1H), 7.92 (d, 1H), 7.61–7.44 (m, 3H), 7.19 (d, 1H), 2.21(s, 3H); MSm/z383 (M+1).

e)1-[2-(3-Bromo-4-chlorophenyl)-7-(cyclopentylamino)pyrazolo[1,5-a]pyridin-3-yl]ethanone

In a similar manner as described in Example 11-[2-(3-bromo-4-chlorophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]ethanone(12.5 g, 32.5 mmol),1-[2-(3-bromo-4-chlorophenyl)-7-(cyclopentylamino)pyrazolo[1,5-a]pyridin-3-yl]ethanonewas obtained as a yellow foam. ¹H NMR (CDCl₃): δ 7.91 (d, 1H), 7.62–7.41(m, 4H), 6.16 (d, 1H), 6.02 (d, 1H), 4.00 (m, 1H), 2.22 (s, 3H), 2.13(m, 2H), 1.82–1.65 (m, 6H), MS m/z 432 (M+1).

f)(2E)-1-[2-(3-Bromo-4-chlorophenyl)-7-(cyclopentylamino)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one

In a similar manner as described in Example 1 from1-[2-(3-bromo-4-chlorophenyl)-7-(cyclopentylamino)pyrazolo[1,5-a]pyridin-3-yl]ethanone,(2E)-1-[2-(3-bromo-4-chlorophenyl)-7-(cyclopentylamino)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one(6.45 g, combined yield for steps e and f 41%) was obtained as a brownsyrup. ¹H NMR (CDCl₃): δ 8.08 (d, 1H), 7.69–7.57 (m, 3H), 7.51 (d, 1H),7.32 (t, 1H), 6.04 (d, 1H), 5.96 (d, 1H), 5.13 (d, 1H), 4.00 (m, 1H),3.0 (b, 3H), 2.62 (b, 3H), 2.13 (m, 2H), 1.84–1.68 (m, 6H); MS m/z 487(M+1).

g)2-(3-Bromo-4-chlorophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine

In a similar manner as described in Example 1 from(2E)-1-[2-(3-bromo-4-chlorophenyl)-7-(cyclopentylamino)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one(3.00 g, 6.15 mmol),2-(3-bromo-4-chlorophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1.5-a]pyridin-7-amine(2.71 g, 80%) was obtained as a yellow solid. ¹H NMR (CDCl₃): δ 8.08 (d,1H), 8.02 (s, 1 H), 7.64 (d, 1H), 7.50 (m, 2H), 7.53 (t, 1H), 6.38 (d,1H), 6.05 (d, 1H), 6.00 (d, 1H), 5.13 (d, 1H), 4.28 (m, 1H), 4.01 (m,1H), 2.15 (m, 2H), 2.04 (m, 2H), 1.83–1.49 (m, 12H); MS m/z 551 (M+1).

EXAMPLE 442-(3-Amino-4-chlorophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine

a)2-{4-Chloro-3-[(diphenylmethylene)amino]phenyl}-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine

In a similar manner as described in Example 16 from2-(3-bromo-4-chlorophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine(0.5 g, 0.91 mmol) was obtained2-{4-chloro-3-[(diphenylmethylene)amino]phenyl}-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-aminewhich was used directly in the next step.

b)2-(3-Amino-4-chlorophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine

In a similar manner as described in Example 16 from2-{4-chloro-3-[(diphenyl-methylene)amino]phenyl}-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-aminewas obtained2-(3-amino-4-chlorophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine(130 mg, yield 29% for 2 steps) as a yellow solid. ¹H NMR (CDCl₃): δ8.00 (d, 1H), 7.75 (d, 1H), 7.42 (m, 1H), 7.28 (m, 2H), 6.92 (d, 1H),6.35 (d, 1H), 6.03 (m, 2H), 5.16 (d, 1H), 4.43 (m, 1H), 4.13 (broad,2H), 3.99 (m, 1H), 2.14–2.08 (m, 4H), 1.80–1.52 (m, 12H). MS m/z488(M+1).

EXAMPLE 452-[4-(Benzylamino)phenyl]-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]-pyrazolo[1,5-a]pyridin-7-amine

In a similar manner as described in Example 17 fromN-{4-[2-(4-aminophenyl)-7-(butylamino)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-butylamine(100 mg, 0.23 mmol), and benzaldehyde (35 μL, 0.35 mmol) was prepared2-[4-(benzylamino)phenyl]-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine(113.6 mg, 94%) as a pale yellow foam. ¹H NMR (CDCl₃): δ 7.94 (d, 1 H),7.77 (d, 1 H), 7.46–7.26 (m, 8 H), 6.70 (d, 2 H), 6.42 (d, 1 H), 6.05(t, 1 H), 5.99 (d, 1 H), 4.40 (d, 2 H), 4.23 (t, 1 H), 3.51 (q, 2 H),3.36 (q, 2 H), 1.79–1.41 (m, 8 H), 0.98 (t, 6 H); MS m/z 520 (M+1).

EXAMPLE 46N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-7-amine

a) 2-(6-Chloro-2-pyridinyl)-1-(3-methylphenyl)ethanone

In a similar manner as described in Example 1 from ethyl3-methylbenzoate (30 g, 183 mmol) was obtained2-(6-chloro-2-pyridinyl)-1-(3-methylphenyl)ethanone (33.6 g, 75% yield)as a mixture of ketone and enol tautomers. This mixture was useddirectly in the next step.

b) 2-(6-Chloro-2-pyridinyl)-1-(3-methylphenyl)ethanone oxime

In a similar manner as described in Example 1 from2-(6-chloro-2-pyridinyl)-1-(3-methylphenyl)ethanone (33.6 g, 137 mmol)was obtained 2-(6-chloro-2-pyridinyl)-1-(3-methylphenyl)ethanone oxime(26.1 g, 73% yield) as a white solid. ¹H NMR (CDCl₃): δ 7.54–7.47 (m,3H), 7.26–7.15 (m, 4H), 4.40 (s, 2H), 2.34 (s, 3H), MS m/z 243 (M+1).

c) 7-Chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridine

In a similar manner as described in Example 1 from2-(6-chloro-2-pyridinyl)-1-(3-methylphenyl)ethanone oxime (13 g, 50mmol) was obtained 7-chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridine(11.5 g, 99% yield) as a yellow crystalline solid. ¹H NMR (CDCl₃): δ7.86 (s, 1H), 7.79 (d, 1H), 7.48 (d, 1H), 7.34 (t, 1H), 7.20 (d, 1H),7.05 (dd, 1H), 6.91 (s, 1H), 6.88 (d, 1H), 2.44 (s, 3H). MS m/z 243(M+1).

d) 7-Chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde

N,N-Dimethylformamide (150 mL) was cooled to 0° C. and treated withphosphorous oxychloride (8.8 mL, 94 mmol). After the addition wascomplete, the mixture was warmed to room temperature and stirred for 1hour. To this was added7-chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridine (16.3 g, 67 mmol) andthe resultant solution was stirred overnight. Water was added, followedby dichloromethane. The aqueous layer was extracted withdichloromethane. The combined organics were washed with brine, driedover magnesium sulfate, filtered and concentrated. The residue wasrecrystallized from diethyl ether and hexanes to give7-chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (14.3g, 79%) as a pale yellow solid. ¹H NMR (CDCl₃): δ 10.11 (s, 1 H), 8.41(dd, 1H), 7.63 (s, 1H), 7.58 (d, 1H), 7.49 (dd, 1H), 7.42 (t, 1H), 7.33(d, 1H), 7.20 (dd, 1H), 2.45 (s, 3H); MS m/z 271 (M+1).

e)1-[7-Chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol

To a cold (−78° C.) suspension of7-chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (10.38g, 36.2 mmol) in tetrahydrofuran (80 mL) was added ethynylmagnesiumbromide (87 mL, 0.5 M in tetrahydrofuran, 43.4 mmol) dropwise. Thereaction mixture was stirred at −78° C. for 1 hour, then at 0° C. for 2hours. The resultant solution was poured into saturated aqueous sodiumbicarbonate and extracted with ethyl acetate. The organic layer waswashed with water and brine and the combined organics were dried overmagnesium sulfate. Filtration and concentration followed by flashchromatography (4:1 hexanes:ethyl acetate to 7:3 hexanes:ethyl acetate)provided1-[7-chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol(11.3 g, 77%) as a yellow foam. ¹H NMR (CDCl₃) δ 8.03 (d, 1H), 7.60 (s,1H), 7.54 (d, 1H), 7.37 (t, 1H), 7.26 (d, 1H), 7.17 (dd, 1H), 6.98 (d,1H), 2.67 (s, 1H), 2.43 (s, 3H), 2.38 (s, 1H); MS m/z297 (M+1).

f)1-[7-Chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one

To a solution of1-[7-chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol(11.3 g, 36.2 mmol) in chloroform (300 mL) was added manganese dioxide(78.9 g, 905 mmol). The reaction mixture was stirred at room temperaturefor 18 hours. The suspension was filtered through a pad of Celite andthe filtrate was concentrated and purified by flash chromatography (7:3hexanes:ethyl acetate).1-[7-chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one(4.57 g, 41%) was obtained as a pale yellow crystalline. ¹H NMR (CDCl₃)δ 8.48 (d, 1H), 7.51 (m, 3H), 7.33 (t, 1H), 7.29 (d, 1H), 8.21 (dd, 1H),2.89 (s, 1H), 2.42 (s, 3H); MS m/z 295 (M+1).

g)4-[7-Chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine

To a solution of1-[7-chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one(4.04 g, 13.0 mmol) in N,N-dimethylformamide (100 mL) was addedcyclopentyl guanidine hydrochloride (6.36 g, 39 mmol), followed by solidpotassium carbonate (5.39 g, 39 mmol). The resultant solution was heatedto reflux for 6 hours. Upon cooling to room temperature, ether was addedfollowed by water. The organics were washed with brine, and the aqueousextracted with ethyl acetate. The combined organics were dried overmagnesium sulfate, filtered and concentrated in vacuo. The residue waspurified by silica gel flash chromatography (3:10 ethyl acetate:hexanes)to give4-[7-chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(2.39 g, 43%) as a yellow foam. ¹H NMR (CDCl₃) δ 8.47 (d, 1H), 7.99 (d,1H), 7.48 (s, 1H), 7.39 (d, 1H), 7.33–7.24 (m, 3H), 7.05 (d, 1H), 6.33(d, 1H), 5.38 (broad s, 1H), 4.36 (m, 1H), 2.40 (s, 3H), 2.10 (m, 2H),1.78 (m, 2H), 1.67 (m, 2H), 1.58 (m, 2H); MS m/z 404 (M+1).

h)N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(3-methylphenyl)-pyrazolo[1,5-a]pyridin-7-amine

To a solution of4-[7-chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(500 mg, 1.24 mmol) in cyclopentylamine (50 mL) was added successivelyracemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (308 mg, 0.49 mmol),cesium carbonate (0.81 g, 2.47 mmol) and palladium (II) acetate (70 mg,0.31 mmol). The resultant mixture was heated to 95° C. for 18 hours atwhich time the reaction was judged complete by thin layerchromatography. The solution was cooled to room temperature and etherwas added. The organic layer was washed with water and brine. Theaqueous layer was extracted with ether and the combined organics driedover magnesium sulfate. Filtration and concentration, followed by flashchromatography (4:1 hexanes:ethyl acetate) providedN-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-7-amine(360 mg, 64%) as a yellow foam. ¹H NMR (CDCl₃) δ 7.94 (d, 1H), 7.79 (d,1H), 7.46 (s, 1H), 7.40 (d, 1H), 7.34–7.29 (m, 2H), 7.24 (d, 1H), 6.27(d, 1H), 6.03 (m, 2H), 5.12 (broad s, 1H), 4.35 (m, 1H), 3.99 (m, 1H),2.40 (s, 3H), 2.14–2.04 (m, 4H), 1.81–1.52 (m, 12H); MS m/z 453 (M+1).

EXAMPLE 474-[7-Chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-5,6-dimethyl-2-pyrimidinamine

a)(2E)-1-[7-Chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-methyl-2-buten-1-oland(2Z)-1-[7-chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-methyl-2-buten-1-ol

To a cold (−78 ° C.) solution of7-chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (592mg, 2.19 mmol) in tetrahydrofuran (6 mL) was added1-methyl-1-propenylmagnesium bromide (12 mL, 0.5 M in tetrahydrofuran, 6mmol existing as a mixture of E and Z isomers). The reaction mixture wasallowed to warm to −20 ° C., then poured into ice water. The aqueousmixture was extracted with ethyl acetate. The combined extracts werewashed with water and brine. The organic layer was dried over magnesiumsulfate. Filtration and concentration followed by flash chromatography(4:1 hexanes:ethyl acetate) provided an inseparable mixture of(2E)-1-[7-chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-methyl-2-buten-1-oland(2Z)-1-[7-chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-methyl-2-buten-1-ol(650 mg, 91%) as a white gummy solid. R_(f) 0.42 (4:1 hexanes:ethylacetate); (for the major isomer) ¹H NMR (CDCl₃) δ 7.97 (d, 1H), 7.45 (s,1H), 7.41 (d, 1H), 7.31 (t, 1H), 7.20 (d, 1H), 7.07 (dd, 1H), 6.90 (d,1H) 6.02 (s, 1H), 5.44 (q, 1H), 2.39 (s, 3H), 1.73 (m, 3H), 1.61 (m,3H); MS m/z 327 (M+1).

b)(2E)-1-[7-Chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-methyl-2-buten-1-oneand(2Z)-1-[7-chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-methyl-2-buten-1-one

To a cold (0 ° C.) solution of a mixture of(2E)-1-[7-chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-methyl-2-buten-1-oland(2Z)-1-[7-chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-methyl-2-buten-1-ol(640 mg, 1.96 mmol) in chloroform (70 mL) was added manganese dioxide(6.5 g, 75 mmol). The reaction mixture was warmed to room temperatureand stirred 16 hours. Additional manganese dioxide (5.0 g, 57 mmol) wasadded and the resultant mixture was stirred at room temperature for 24hours. The reaction mixture was filtered through a pad of Celite. Thefiltrate was concentrated in vacuo to provide an inseparable mixture of(2E)-1-[7-chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-methyl-2-buten-1-oneand(2Z)-1-[7-chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-methyl-2-buten-1-one(635 mg, 100%) as a white solid. R_(f) 0.45 (4:1 hexanes:ethyl acetate);(for the major isomer) ¹H NMR (CDCl₃) δ 8.27 (d, 1H), 7.43–7.39 (m, 3H),7.32–7.27 (m, 2H), 7.14 (d, 1H), 5.35 (q, 1H), 2.39 (s, 3H), 1.73 (m,3H), 1.48 (m, 3H); MS m/z 325 (M+1).

c)4-[7-Chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-5,6-dimethyl-2-pyrimidinamine

To a suspension of N-cyclopentylguanidine hydrochloride (261 mg, 1.60mmol) in ethanol (2 mL) was added sodium ethoxide (530 μL, 3 M inethanol, 1.6 mmol). The mixture was stirred at room temperature for 10minutes. To this suspension was added a mixture of(2E)-1-[7-chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-methyl-2-buten-1-oneand(2Z)-1-[7-chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-methyl-2-buten-1-one(200 mg, 0.616 mmol) portionwise. The reaction mixture was stirred at70° C. for 16 hours then cooled to room temperature. Palladium on carbon(10%, 230 mg) was added and the reaction mixture was stirred at 60° C.for 24 hours. The reaction mixture was diluted with ethanol (15 mL) andfiltered through Celite. The filtrate was concentrated in vacuo andchromatographed (39:1 dichloromethane:methanol) to provide4-[7-chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-5,6-dimethyl-2-pyrimidinamine(80 mg, 30%) as a light brown solid. R_(f) 0.47 (29:1dichloromethane:methanol); ¹H NMR (CDCl₃) δ 7.60 (s, 1H), 7.55 (d, 1H),7.32 (d, 1H), 7.21–7.11 (m, 3H), 6.96 (d, 1H), 4.99 (broad, 1H), 4.28(m, 1H); 2.35 (s, 3H), 2.30 (s, 3H), 2.01 (m, 2H), 1.74–1.42 (9 H); MSm/z 432 (M+1).

EXAMPLE 48N-cyclopentyl-3-[2-(cyclopentylamino)-5,6-dimethyl-4-pyrimidinyl]-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-7-amine

A mixture of4-[7-chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-5,6-dimethyl-2-pyrimidinamine(80 mg, 0.19 mmol) and cyclopentylamine (2 mL, 20 mmol) was heated in asealed tube at 90° C. for 3 hours followed by 125° C. for 24 hours. Thereaction mixture was cooled to room temperature and excesscyclopentylamine was removed in vacuo. The crude residue was washed withsaturated aqueous sodium bicarbonate solution. The aqueous layer wasextracted with ethyl acetate. The combined extracts were washed withwater and brine then dried over magnesium sulfate. Filtration andconcentration followed by flash chromatography (5:1 hexanes:ethylacetate) providedN-cyclopentyl-3-[2-(cyclopentylamino)-5,6-dimethyl-4-pyrimidinyl]-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-7-amine(40 mg, 44%) as a clear oil. R_(f) 0.32 (4:1 hexanes:ethyl acetate); ¹HNMR (CDCl₃) δ 7.57 (s, 1H), 7.33 (d, 1H), 7.19–7.11 (m, 3H), 6.91 (d,1H), 6.03 (d, 1H), 6.93 (d, 1H), 4.91 (d, 1H), 4.29 (m, 1H), 4.01 (m,1H), 2.34 (s, 3H), 2.28 (s, 3H), 2.15 (m, 2H), 1.99 (broad, 2H),1.87–1.40 (m, 15H); MS m/z 481 (M+1). To a solution of the product (20mg) in ether was added 1 M HCl in ether. The precipitated solid wasisolated to give the corresponding HCl salt.

EXAMPLE 493-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-isopropyl-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-7-amine

In a similar manner as described in Example 46 from4-[7-chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(100 mg, 0.25 mmol) and isopropylamine was obtained3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-isopropyl-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-7-amine(36 mg, 34%) as a yellow foam. ¹H NMR (CDCl₃) δ 7.97 (d, 1H), 7.79 (d,1H), 7.47 (s, 1H), 7.41 (d, 1H), 7.34–7.23 (m, 3H), 6.28 (d, 1H), 6.00(d, 1H), 5.98 (d, 1H), 5.14 (d, 1H), 4.35 (m, 1H), 3.85 (m, 1H), 2.40(s, 3H), 2.07 (m, 2H), 1.75 (m, 2H), 1.66 (m, 2H), 1.56 (m, 2H), 1.36(d, 6H); MS m/z 427 (M+1).

EXAMPLE 504-[7-Chloro-2-(3-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine

a) 2-(6-Chloro-2-pyridinyl)-1-(3-methoxyphenyl)ethanone

In a similar manner as described in Example 1 from ethyl3-methoxybenzoate (30 g, 166 mmol) and 6-chloropicoline (21.2 g, 166mmol) was obtained 2-(6-chloro-2-pyridinyl)-1-(3-methoxyphenyl)ethanoneas a mixture of ketone and enol tautomers. This product was useddirectly in the next step.

b) 2-(6-Chloro-2-pyridinyl)-1-(3-methoxyphenyl)ethanone oxime

In a similar manner as described in Example 1 from2-(6-chloro-2-pyridinyl)-1-(3-methoxyphenyl)ethanone was obtained2-(6-chloro-2-pyridinyl)-1-(3-methoxyphenyl)ethanone oxime (33.1 g,yield for the two steps 72%) as a white solid. ¹H NMR (CDCl₃) δ 8.22(broad s, 1H), 7.52 (t, 1H), 7.34 (m, 1H), 7.26–7.25 (m, 2H), 7.17–7.05(d, 2H), 6.90 (m, 1H), 4.36 (s, 2H), 3.81 (s, 3H); MS m/z 277.

c) 7-Chloro-2-(3-methoxyphenyl)pyrazolo[1,5-a]pyridine

In a similar manner as described in Example 1 from2-(6-chloro-2-pyridinyl)-1-(3-methoxyphenyl)ethanone oxime (33.0 g, 119mmol) was obtained 7-chloro-2-(3-methoxyphenyl)pyrazolo[1,5-a]pyridine(23.1 g, 75% yield) as a pale yellow solid. ¹H NMR (CDCl₃) δ 7.59 (m,2H), 7.49 (d, 1H), 7.37 (t, 1H), 7.07 (t, 1H), 6.95–6.94 (dd, 1H), 6.91(s, 1H), 6.88 (d, 1H), 3.90 (s, 3H); MS m/z 259.

d) 7-Chloro-2-(3-methoxyphenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde

In a similar manner as described in Example 46 from7-chloro-2-(3-methoxyphenyl)pyrazolo[1,5-a]pyridine (23 g, 88.9 mmol)was obtained7-chloro-2-(3-methoxyphenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (21.6g. 84%) as a white solid. ¹H NMR (CDCl₃) δ 10.13 (s, 1H), 8.40 (d, 1H),7.52–7.42 (m, 2H), 7.35 (m, 2H), 7.21 (d, 1H), 7.06 (d, 1H), 3.89 (s,3H); MS m/z 287.

e)1-[7-Chloro-2-(3-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol

In a similar manner as described in Example 46 from7-chloro-2-(3-methoxyphenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde(17.25 g, 60.1 mmol) and ethynylmagnesium bromide was obtained1-[7-chloro-2-(3-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol(19.0 g, 100%). ¹H NMR (CDCl₃) δ 8.02 (d, 1H), 7.38–7.32 (m, 3H), 7.17(t, 1H), 6.98–6.97 (d, 2H), 5.82 (m, 1H), 3.86 (s, 3H), 2.67 (s, 1H),2.53 (d, 1H); MS m/z 313.

f)1-[7-Chloro-2-(3-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one

In a similar manner as described in Example 46 from1-[7-chloro-2-(3-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol(19 g, 60.8 mmol) was obtained1-[7-chloro-2-(3-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one(14.4 g, yield 76%) as an orange colored solid. ¹H NMR (CDCl₃) δ 8.47(d, 1H), 7.52 (t, 1H), 7.36 (t, 1H), 7.29–7.21 (m, 3H), 7.02 (dd, 1H),3.86 (s, 3H), 2.92 (s, 1H); MS m/z 311.

g)4-[7-Chloro-2-(3-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine

In a similar manner as described in Example 46 from1-[7-chloro-2-(3-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one(1.0 g, 3.2 mmol) and cyclopentyl guanidine hydrochloride was obtained4-[7-chloro-2-(3-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(0.34 g, yield 25%) as a pale yellow foam. ¹H NMR (CDCl₃) δ 8.52 (d,1H), 8.05 (d, 1H), 7.43–7.23 (m, 4H), 7.11 (d, 1H), 7.03 (dd, 1H), 6.40(d, 1H), 5.45 (broad s, 1H), 4.40 (m, 1H), 3.86 (s. 3H), 2.10 (m, 2H),1.85–1.59 (m, 6H); MS m/z 420.

EXAMPLE 51N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(3-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine

In a similar manner as described in Example 1 from4-[7-chloro-2-(3-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(500 mg, 1.19 mmol) and cyclopentylamine was obtainedN-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(3-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine(389 mg, yield 70%) as a yellow foam. ¹H NMR (CDCl₃) δ 7.92 (d, 1H),7.79 (d, 1H), 7.38–7.30 (m, 2H), 7.21–7.18 (m, 2H), 6.99 (d, 1H), 6.30(d, 1H), 6.04 (m, 2H), 5.38 (broad s, 1H), 4.36 (m, 1H), 4.00 (m, 1H),3.82 (s, 3H), 2.14–2.06 (m, 4H), 1.82–1.57 (m, 12H); MS m/z 469.

EXAMPLE 523-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-isopropyl-2-(3-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine

In a similar manner as described in Example 1 from4-[7-chloro-2-(3-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(150 mg, 0.36 mmol) and isopropylamine was obtained3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-isopropyl-2-(3-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine(98 mg, yield 62%) as a yellow foam. ¹H NMR (CDCl₃) δ 7.93 (s,1H), 7.78(d, 1H), 7.38–7.31 (m, 2H), 7.22–7.18 (m, 2H), 6.99 (d, 1H), 6.30 (d,1H), 6.03 (d, 1H), 5.96 (d, 1H), 5.30 (broad s, 1H), 4.36 (m, 1H), 3.85(m, 1H), 3.82 (s, 3H), 2.10–2.06 (m, 2H), 1.76–1.53 (m, 6H), 1.37 (d,6H); MS m/z 443.

EXAMPLE 533-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(3-methoxyphenyl)-N,N-dimethylpyrazolo[1,5-a]pyridin-7-amine

To a solution of4-[7-chloro-2-(3-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(60 mg, 0.14 mmol) in N,N-dimethylformamide (10 mL) was addeddimethylamine (7 mL 40% in water). The solution was heated in a stealbomb at 100° C. for 3 days. The bomb was cooled to room temperature andethyl acetate was added to the reaction mixture. The organics werewashed with water, brine and dried over magnesium sulfate. Filtrationand concentration followed by purification with flash chromatography(95:5-dichloromethane: methanol) gave3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(3-methoxyphenyl)-N,N-dimethylpyrazolo[1,5-a]pyridin-7-amine(43 mg, 70%) as a yellow foam. ¹H NMR (CDCl₃) δ 8.11 (d, 1H), 7.95 (s,1H), 7.35–7.30 (m, 2H), 7.24–7.21 (m, 2H), 6.97 (dd, 1H), 6.36 (d, 1H),6.32 (d, 1H), 5.40 (broad s, 1H), 4.37 (m, 1H), 3.80 (s, 3H), 3.12 (s,6H), 2.11–2.06 (m, 2H), 1.77–1.56 (m, 6H); MS m/z 429.

EXAMPLE 543-{7-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenol

In a similar manner as described in Example 4 fromN-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(3-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine(150 mg, 0.32 mmol) was obtained3-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenol(126 mg, yield 87%) as a yellow foam. ¹H NMR (CDCl₃) δ 7.83 (d, 1H),7.77 (d, 1H), 7.35–7.28 (m, 2H), 7.21 (d, 1H), 7.06 (s, 1H), 6.95 (dd,1H), 6.39 (d, 1H), 6.05–6.02 (m, 2H), 5.29 (s, 1H), 5.22 (m, 1H), 4.31(m, 1H), 3.99 (m, 1H), 2.12–1.98 (m, 4H), 1.80–1.46 (m, 12H); MS m/z455.

EXAMPLE 55N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[3-(cyclopropylmethoxy)phenyl]pyrazolo[1,5-a]pyridin-7-amine

To a solution of3-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenol(400 mg, 0.88 mmol) in acetonitrile (80 mL) was added cesium carbonate(315 mg, 0.97 mmol) and (bromomethyl)-cyclopropane (0.26 mL, 2.64 mmol).The reaction mixture was heated at reflux for 6 hours. After thereaction was cooled to room temperature, ethyl acetate was added and theorganic phase was washed with water, brine and dried over magnesiumsulfate. Filtration and concentration followed by purification withsilica gel chromatography (3:2 hexanes/ethyl acetate) gaveN-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[3-(cyclopropylmethoxy)phenyl]pyrazolo[1,5-a]pyridin-7-amine(320 mg, 71%) as yellow solid. ¹H NMR (CDCl₃): δ 7.97 (d, 1H), 7.78 (d,1H), 7.33 (m, 2H), 7.18 (m, 2H), 6.98 (m, 1H), 6.30 (d, 1H), 6.02 (m,2H), 5.08 (d, 1), 4.35 (m, 1H), 3.99 (m, 1H), 3.80 (d, 2H), 2.014 (m,4H), 1.83–1.55 (m, 12H), 1.22 (m, 1H), 0.61 (m, 2H), 0.35 (m, 2H). MSm/z 509 (M+1).

EXAMPLE 56N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(3-fluorophenyl)pyrazolo[1,5-a]pyridin-7-amine

In a similar manner as described for above examples the title compoundwas prepared as a yellow solid. R_(f) 0.43 (99:1dichloromethane:methanol); ¹H NMR (CDCl₃): δ 8.06 (d, 1H), 7.76 (d, 1H),7.47–7.30 (m, 4H), 7.17 (m, 1H), 6.35 (d, 1H), 6.10–6.04 (m, 2H), 5.15(d, 1H), 4.36 (m, 1H), 4.05 (m, 1H), 2.21–2.07 (m, 4H), 1.88–1.54 (m,12H), MS m/z 457 (M+1).

EXAMPLE 572-(3-Chlorophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine

In a similar manner as described for above examples the title compoundwas prepared as a yellow solid. R_(f) 0.48 (49:1dichloromethane:methanol); ¹H NMR (DMSO-d₆) δ 8.02 (d, 1H), 7.73–7.67(br, 2H), 7.56–7.44 (m, 2H), 7.36 (t, 1H), 7.01 (d, 1H), 6.61 (d, 1H),6.22–6.17 (m, 2H), 4.09 (br, 1H), 3.98 (m, 1H), 2.04 (m, 2H), 1.84 (m,2H), 1.72–1.48 (m, 12H); MS m/z 473 (M+1). Anal. Calcd for C₂₇H₂₉ClN₆:C, 68.56; H, 6.18; N, 17.77. Found: C, 68.55; H, 6.20; N, 17.64.

EXAMPLE 58N-Cyclopentyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine

In a similar manner as described in Example 1 from(2E)-1-[7-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one(0.25 g, 0.62 mmol) and N-cyclopropylguanidine sulfate was obtainedN-cyclopentyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine(0.11 g, 41%) as a light yellow solid. ¹H NMR (CDCl₃): δ 7.95 (m, 2 H),7.57 (d, 2 H), 7.31 (t, 1 H), 6.90 (d, 2 H), 6.37 (d, 1 H), 6.04 (m,2H), 4.00 (m, 1 H), 3.87 (s, 3 H), 2.87 (m, 1 H), 2.12 (m, 2 H),1.82–1.55 (m, 6 H), 0.87 (m, 2 H), 0.64 (m, 2 H); MS m/z 441 (M+1).

EXAMPLE 593-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)-N-[2-(4-morpholinyl)ethyl]pyrazolo[1,5-a]pyridin-7-amine

a) 7-Chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde

In a similar manner as described in Example 46 from7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridine (5.0 g, 19.3 mmol)was obtained7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (5.11g, 92%) as a pale yellow crystalline solid. ¹H NMR (CDCl₃): δ 10.14 (s,1 H), 8.40 (d, 1 H), 7.78 (d, 2 H), 7.50 (t, 1 H), 7.21 (d, 1 H), 7.08(d, 2 H), 3.91 (s, 3 H); MS m/z 287 (M+1).

b)1-[7-Chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol

In a similar manner as described in Example 46 from7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (5.11g, 17.8 mmol) and ethynylmagnesium bromide (89 mL, 0.5 M intetrahydrofuran, 44.6 mmol) at 0° C. was obtained1-[7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol(5.22 g, 94%) as an off-white solid. ¹H NMR (CDCl₃): δ 8.02 (d, 1 H),7.73 (d, 2 H), 7.18 (t, 1 H), 7.02 (d, 2 H), 6.97 (d, 1 H), 5.79 (m, 1H), 3.87 (s, 3 H), 2.68 (m, 1 H), 2.25 (d, 1H).

c)1-[7-Chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one

In a similar manner as described in Example 46 from1-[7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol(5.22 g, 16.7 mmol) and manganese dioxide (58.0 g, 668 mmol) indichloromethane (250 mL) was obtained1-[7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one(3.46 g, 67%) as a gold solid. ¹H NMR (CDCl₃): δ 8.47 (d, 1 H), 7.67 (d,2 H), 7.50 (t, 1 H), 7.20 (d, 1 H), 6.98 (d, 2 H), 3.87 (s, 3 H), 2.97(s, 1 H); MS m/z 333 (M+1).

d)4-[7-Chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine

To a mixture of1-[7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one(1.57 g, 5.0 mmol) and N-cyclopentylguanidine hydrochloride (1.07 g, 6.6mmol) in ethanol (50 mL) was added sodium ethoxide (2.5 mL, 21 wt % inethanol, 6.6 mmol). The resulting suspension was stirred overnight atroom temperature, then diluted with water and extracted with ethylacetate. The organic extracts were washed with brine and dried overmagnesium sulfate. Filtration and concentration followed by flashchromatography (7:3 to 3:2 hexanes-ethyl acetate) provided4-[7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(1.77 g, 83%) as a pale yellow solid. ¹H NMR (CDCl₃): δ 8.44 (d, 1 H),8.05 (d, 1 H), 7.60 (d, 2 H), 7.28 (m, 1 H), 7.06–6.96 (m, 3 H), 6.38(d, 1 H), 5.31 (broad, 1 H), 4.38 (m, 1 H), 3.88 (s, 3 H), 2.12 (m, 2H), 1.84–1.53 (m, 6 H); MS m/z 420 (M+1).

e)3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)-N-[2-(4-morpholinyl)ethyl]pyrazolo[1,5-a]pyridin-7-amine

A mixture of4-[7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(150 mg, 0.36 mmol) and 4-(2-aminoethyl)morpholine (3 mL, 21.2 mmol) washeated at 140° C. for 4 hours. Concentration of the reaction mixturefollowed by flash chromatography (3:1 ethyl acetate-hexane to ethylacetate) provided3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)-N-[2-(4-morpholinyl)ethyl]pyrazolo[1,5-a]pyridin-7-amine(135 mg, 74%) as a pale yellow foam. ¹H NMR (CDCl₃): δ 8.01 (d, 1 H),7.78 (d, 1 H), 7.61 (d, 2 H), 7.30 (t, 1 H), 6.99 (d, 2 H), 6.52 (t, 1H), 6.36 (d, 1 H), 5.98 (d, 1 H), 5.08 (d, 1 H), 4.37 (m, 1 H), 3.88 (s,3 H), 3.76 (m, 4 H), 3.46 (q, 2 H), 2.76 (t, 2 H), 2.54 (m, 4 H),2.12–1.52 (m, 8 H); MS m/z 514 (M+1).

EXAMPLE 603-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-cyclopropyl-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine

To a solution of4-[7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(0.39 g, 0.93 mmol) in toluene (20 mL) was added successivelyracemic-BINAP (34.7 mg, 0.06 mmol), cesium carbonate (0.91 g, 2.8 mmol),cyclopropylamine (0.64 mL, 9.3 mmol) and palladium (II) acetate (8.3 mg,0.04 mmol). The resultant mixture was heated under reflux for 8 hours.After cooling to room temperature the reaction mixture was partitionedbetween ether and water. The organic layer was washed with brine anddried over magnesium sulfate. Filtration and concentration followed byflash chromatography (3:1 hexanes-ethyl acetate) provided3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-cyclopropyl-2-(4-methoxyphenyl)pyrazolo-[1,5-a]pyridin-7-amine(0.30 g, 73%) as a pale yellow solid. ¹H NMR (CDCl₃): δ 7.95 (d, 1 H),7.85 (d, 1 H), 7.56 (d, 2 H), 7.36 (t, 1 H), 6.99 (d, 2 H), 6.40 (d, 1H), 6.33 (m, 2 H), 4.38 (m, 1 H), 3.88 (s, 3 H), 2.68 (m, 1 H), 2.09 (m,2H), 1.81–1.57 (m, 6 H), 0.89 (m, 2 H), 0.75 (m, 2 H); MS m/z 441 (M+1).

EXAMPLE 61N-Cyclopentyl-4-[2-(4-methoxyphenyl)-7-(4-morpholinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

A mixture of4-[7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(75 mg, 0.18 mmol) and morpholine (5 mL, 57 mmol) was heated at 120° C.for 4 hours, then cooled and concentrated. Flash chromatography (3:1 to1:3 hexanes-ethyl acetate) affordedN-cyclopentyl-4-[2-(4-methoxyphenyl)-7-(4-morpholinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(72 mg, 86%) as a yellow solid. ¹H NMR (CDCl₃): δ 8.14 (d, 1 H), 7.93(broad, 1 H), 7.58 (d, 2 H), 7.33 (t, 1 H), 6.97 (d, 2 H), 6.35 (m, 2H), 4.38 (m, 1 H), 3.99 (m, 4 H), 3.87 (s, 3 H), 3.50 (m, 4 H), 2.08 (m,2 H), 1.79–1.54 (m, 6 H); MS m/z 471 (M+1).

EXAMPLE 623-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-(2-methoxyethyl)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine

A mixture of4-[7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(75 mg, 0.18 mmol) and 2-methoxyethylamine (5 mL, 58 mmol) was heated at90° C. for 72 hours, then cooled and concentrated. Flash chromatography(1:1 to 1:3 hexanes-ethyl acetate) provided3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-(2-methoxyethyl)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine(80.4 mg, 98%) as an off-white solid. ¹H NMR (CDCl₃): δ 7.98 (d, 1 H),7.81 (d, 1 H), 7.59 (d, 2 H), 7.31 (t, 1 H), 6.99 (d, 2 H), 6.35–6.29(m, 2 H), 6.03 (d, 1 H), 5.15 (broad, 1 H), 4.38 (m, 1 H), 3.89 (s, 3H), 3.72 (t, 2 H), 3.57 (q, 2 H), 3.43 (s, 3 H), 2.09 (m, 2 H),1.80–1.53 (m, 6 H); MS m/z 459 (M+1).

EXAMPLE 63N-Cyclopropyl-4-[2-(4-methoxyphenyl)-7-(4-morpholinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

a)4-[7-Chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl-2-pyrimidinamine

In a similar manner as described in examples above from1-[7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one(1.80 g, 5.8 mmol) and N-cyclopropylguanidine sulfate (1.50 g, 7.5 mmol)was prepared4-[7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl-2-pyrimidinamine(1.31 g, 58%) as a yellow solid. ¹H NMR (CDCl₃): δ 8.61 (broad, 1 H),8.09 (broad, 1 H), 7.59 (d, 2 H), 7.28–7.23 (m, 1 H), 7.03 (d, 1 H),6.98 (d, 2 H), 6.43 (d, 1 H), 5.41 (broad, 1 H), 3.87 (s, 3 H), 2.86 (m,1 H), 0.88 (m, 2 H), 0.65 (m, 2 H); MS m/z 392 (M+1).

b)N-Cyclopropyl-4-[2-(4-methoxyphenyl)-7-(4-morpholinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

A mixture of4-[7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl-2-pyrimidinamine(75 mg, 0.19 mmol) and morpholine (2 mL, 23 mmol) was heated in a sealedtube at 140° C. for 4 hours. After cooling to room temperature, themixture was concentrated. Flash chromatography (1:1 to 1:3 hexanes-ethylacetate) providedN-cyclopropyl-4-[2-(4-methoxyphenyl)-7-(4-morpholinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(78.4 mg, 92%) as an off-white solid. ¹H NMR (CDCl₃): δ 8.29 (d, 1 H),8.08 (d, 1 H), 7.61 (d, 2 H), 7.31 (t, 1 H), 6.98 (d, 2 H), 6.45 (d, 1H), 6.33 (d, 1 H), 5.40 (broad, 1 H), 4.00 (m, 4 H), 3.89 (d, 3 H), 3.51(m, 4 H), 2.88 (m, 1 H), 0.89 (m, 2 H), 0.65 (m, 2 H); MS m/z 443 (M+1).

EXAMPLE 643-[2-(Cyclopropylamino)-4-pyrimidinyl]-N-(2-methoxyethyl)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine

A mixture of4-[7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl-2-pyrimidinamine(75 mg, 0.19 mmol) and 2-methoxyethylamine (5 mL, 58 mmol) was heated ina sealed tube at 140° C. for 24 hours. After cooling to roomtemperature, the mixture was concentrated. Flash chromatography (1:1 to1:3 hexanes-ethyl acetate) provided3-[2-(cyclopropylamino)-4-pyrimidinyl]-N-(2-methoxyethyl)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine(77.7 mg, 95%) as a yellow solid. ¹H NMR (CDCl₃): δ 8.03 (d, 1 H), 7.96(d, 1 H), 7.60 (d, 2 H), 7.31 (t, 1 H), 7.00 (d, 2 H), 6.41 (d, 1 H),6.31 (t, 1 H), 6.04 (d, 1 H), 5.40 (broad, 1 H), 3.89 (s, 3 H), 3.72 (t,2 H), 3.57 (q, 2 H), 3.43 (s, 3 H), 2.88 (m, 1 H), 0.88 (m, 2 H), 0.64(m, 2 H); MS m/z 431 (M+1).

EXAMPLE 653-[2-(Cyclopropylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)-N-[2-(4-morpholinyl)ethyl]pyrazolo[1,5-a]pyridin-7-amine

In a similar manner as described in Example 64 from4-[7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl-2-pyrimidinamine(75 mg, 0.19 mmol) was prepared3-[2-(cyclopropylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)-N-[2-(4-morpholinyl)ethyl]pyrazolo[1,5-a]pyridin-7-amine(74.5 mg, 80%) as a light yellow foam. ¹H NMR (CDCl₃): δ 8.05 (d, 1 H),7.93 (d, 1 H), 7.61 (d, 2 H), 7.31 (t, 1 H), 7.00 (d, 2 H), 6.52 (t, 1H), 6.42 (d, 1 H), 6.00 (d, 1 H), 5.32 (broad, 1 H), 3.89 (s,3 H), 3.76(m, 4 H), 3.46 (q, 2 H), 2.88 (m, 1 H), 2.77 (t, 2 H), 2.55 (m, 4 H),0.88 (m, 2 H), 0.64 (m, 2 H); MS m/z 486 (M+1).

EXAMPLE 66N-Cyclopropyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine

a)1-[7-(Cyclopropylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone

In a similar manner as described in Example 1 from1-[7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone(1.15 g, 3.8 mmol) was prepared1-[7-(cyclopropylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone(1.22 g, 99%) as a thick yellow oil. ¹H NMR (CDCl₃): δ 7.77 (d, 1 H),7.53–7.45 (m, 3 H), 7.03 (d, 2 H), 6.50 (d, 1 H), 6.37 (broad, 1 H),3.89 (s, 3 H), 2.67 (m, 1 H), 2.15 (s, 3 H), 0.89 (m, 2 H), 0.74 (m, 2H); MS m/z 322 (M+1).

b)(2E)-1-[7-(Cyclopropylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one

A solution of1-[7-(cyclopropylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone(1.22 g, 3.8 mmol) in N,N-dimethylformamide di-tert-butyl acetal (8 mL,33 mmol) was heated under reflux for 4 hours. After cooling to roomtemperature, the reaction mixture was diluted with water and extractedwith ethyl acetate. The organics were washed with water and brine, thendried over magnesium sulfate. Filtration and concentration followed byflash chromatography (1:1 hexanes-ethyl acetate to ethyl acetate)provided(2E)-1-[7-(cyclopropylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one(1.19 g, 83%) as a gold foam. ¹H NMR (CDCl₃): δ 7.73 (d, 1 H), 7.62 (d,2 H), 7.34 (t, 1 H), 6.97 (d, 2 H), 6.37 (d, 1 H), 6.29 (s, 1 H), 5.13(d, 1 H), 3.85 (s, 3 H), 2.95 (broad, 3 H), 2.65 (m, 1 H), 2.50 (broad,3 H), 0.86 (m, 2 H), 0.72 (m, 2 H); MS m/z 377 (M+1).

c)N-Cyclopropyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine

In a similar manner as described in Example 1 from(2E)-1-[7-(cyclopropylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one(1.19 g, 3.2 mmol) and N-cyclopropylguanidine sulfate (1.25 g, 6.3 mmol)was preparedN-cyclopropyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine(0.71 g, 55%) as a light yellow foam. ¹H NMR (CDCl₃): δ 8.04 (d, 1 H),7.99 (d, 1 H), 7.57 (d, 2 H), 7.34 (t, 1 H), 6.99 (d, 2 H), 6.39 (m, 2H), 6.33 (s, 1 H), 5.31 (s, 1 H), 3.89 (s, 3 H), 2.88 (m, 1 H), 2.68 (m,1 H), 0.88 (m, 4 H), 0.75 (m, 2 H), 0.64 (m, 2 H); MS m/z 413 (M+1).

EXAMPLE 674-[3-[2-(Cyclopentylamino)-4-pyrimidinyl]-7-(cyclopropylamino)pyrazolo[1,5-a]pyridin-2-yl]phenol

In a similar manner as described in Example 4 from3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-cyclopropyl-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine(0.24 g. 0.54 mmol) was prepared4-[3-[2-(cyclopentylamino)-4-pyrimidinyl]-7-(cyclopropylamino)pyrazolo[1,5-a]pyridin-2-yl]phenol(0.17 g, 72%) as a gold foam. ¹H NMR (CDCl₃): δ 7.96 (d, 1 H), 7.82 (d,1 H), 7.50 (d, 2 H), 7.35 (t, 1 H), 6.91 (d, 2 H), 6.39 (d, 1 H), 6.32(m, 2 H), 5.13 (d, 1 H), 4.38 (m, 1 H), 2.68 (m, 1 H), 2.09 (m, 2 H),1.80–1.53 (m, 6 H), 0.89 (m, 2 H), 0.75 (m, 2 H); MS m/z 427 (M+1).

EXAMPLE 684-{7-(Cyclopentylamino)-3-[2-(cyclopropylamino)-4-pyrimidinyl]-pyrazolo[1,5-a]pyridin-2-yl}phenol

In a similar manner as described in Example 4 fromN-cyclopentyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine(0.19 g, 0.43 mmol) was prepared4-{7-(cyclopentylamino)-3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenol(0.12 g, 67%) as a gold foam. ¹H NMR (CDCl₃): δ 7.97 (d, 1 H), 7.89 (d,1 H), 7.51 (d, 2 H), 7.32 (t, 1 H), 6.94 (d, 2 H), 6.37 (d, 1 H), 6.05(d, 2 H), 5.42 (s, 1 H), 4.01 (m, 1 H), 2.87 (m, 1 H), 2.14 (m, 2 H),1.83–1.55 (m, 6 H), 0.89 (m, 2 H), 0.65 (m, 2 H); MS m/z 427 (M+1).

EXAMPLE 694-{7-(Cyclopropylamino)-3-[2-(cyclopropylamino)-4-pyrimidinyl]-pyrazolo[1,5-a]pyridin-2-yl}phenol

In a similar manner as described in Example 4 fromN-cyclopropyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine(0.33 g, 0.80 mmol) was prepared4-{7-(cyclopropylamino)-3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenol(0.18 9, 56%) as a gold foam. ¹H NMR (CDCl₃): δ 7.98 (m, 2 H), 7.51 (d,2 H), 7.36 (t, 1 H), 6.93 (d, 2 H), 6.42–6.34 (m, 3 H), 5.45 (broad, 1H), 2.88 (m, 1 H), 2.68 (m, 1 H), 0.89 (m, 4 H), 0.76 (m, 2 H), 0.65 (m,2 H); MS m/z 399 (M+1).

EXAMPLE 703-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-cyclopropyl-2-[4-(cyclopropylmethoxy)phenyl]pyrazolo[1,5-a]pyridin-7-amine

To a solution of4-[3-[2-(cyclopentylamino)-4-pyrimidinyl]-7-(cyclopropylamino)pyrazolo[1,5-a]pyridin-2-yl]phenol(146 mg, 0.34 mmol) in N,N-dimethylformamide (3 mL) was added cesiumcarbonate (0.22 g, 0.68 mmol) and (bromomethyl)cyclopropane (66 μL, 0.68mmol). The reaction was stirred for 1 hour at room temperature, thenpartitioned between water and ethyl acetate. The organic layer waswashed with brine and dried over magnesium sulfate. Filtration andconcentration followed by flash chromatography (3:1 to 1:1 hexanes-ethylacetate) provided3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-cyclopropyl-2-[4-(cyclopropylmethoxy)phenyl]pyrazolo[1,5-a]pyridin-7-amine(90.4 mg, 55%) as an off-white solid. ¹H NMR (CDCl₃): δ 7.99 (d, 1 H),7.84 (d, 1 H), 7.55 (d, 2 H), 7.34 (t, 1 H), 6.98 (d, 2 H), 6.39–6.32(m, 3 H), 5.08 (broad, 1 H), 4.37 (m, 1 H), 3.87 (d, 2 H), 2.68 (m, 1H), 2.10 (m, 2 H), 1.80–1.27 (m, 6 H), 0.89 (m, 2 H), 0.78–0.65 (m, 4H), 0.39 (m, 2 H); MS m/z 481 (M+1).

EXAMPLE 712-[4-(Allyloxy)phenyl]-N-cyclopentyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine

In a similar manner as described in Example 70 from4-{7-(cyclopentylamino)-3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenol(90 mg, 0.21 mmol) and allyl bromide (37 μL, 0.42 mmol) was prepared2-[4-(allyloxy)phenyl]-N-cyclopentyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine(76.8 mg, 78%) as a pale yellow solid. ¹H NMR (CDCl₃): δ 7.97–7.94 (m, 2H), 7.57 (d, 2 H), 7.34 (t, 1 H), 7.02 (d, 2 H), 6.39 (d, 1 H),6.16–6.04 (m, 3 H), 5.47 (dd, 1 H), 5.33 (dd, 1 H), 4.62 (d, 2 H), 4.02(m, 1 H), 2.89 (m, 1 H), 2.16 (m, 2 H), 1.83–1.69 (m, 6 H), 0.89 (m, 2H), 0.67 (m, 2 H); MS m/z 467 (M+1).

EXAMPLE 72N-Cyclopropyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]-2-[4-(cyclopropylmethoxy)phenyl]pyrazolo[1,5-a]pyridin-7-amine

In a similar manner as described in Example 70 from4-{7-(cyclopropylamino)-3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenol (102 mg, 0.25 mmol) was preparedN-cyclopropyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]-2-[4-(cyclopropylmethoxy)phenyl]pyrazolo[1,5-a]pyridin-7-amine(78 mg, 68%) as a pale yellow solid. ¹H NMR (CDCl₃): δ 8.00–7.96 (m, 2H), 7.53 (d, 2 H), 7.34 (t, 1 H), 6.97 (d, 2 H), 6.40–6.33 (m, 3 H),5.55 (broad, 1 H), 3.86 (d, 2 H), 2.87 (m, 1 H), 2.66 (m, 1 H), 1.31 (m,1 H), 0.87 (m, 4 H), 0.74 (m, 2 H), 0.66 (m, 4 H), 0.38 (m, 2 H); MS m/z453 (M+1).

EXAMPLE 732-[4-(Allyloxy)phenyl]-N-cyclopropyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine

In a similar manner as described in Example 70 from4-{7-(cyclopropylamino)-3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenol(60 mg, 0.15 mmol) and allyl bromide (26 μL, 0.30 mmol) was prepared2-[4-(allyloxy)phenyl]-N-cyclopropyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine(47 mg, 71%) as a pale yellow foam. ¹H NMR (CDCl₃): δ 8.00–7.97 (m, 2H), 7.54 (d, 2 H), 7.35 (t, 1 H), 7.00 (d, 2 H), 6.41–6.33 (m, 3 H),6.09 (m, 1 H), 5.62 (broad, 1 H), 5.45 (dd, 1 H), 5.32 (d, 1 H), 4.60(d, 2 H), 2.87 (m, 1 H), 2.67 (m, 1 H), 0.87 (m, 4 H), 0.74 (m, 2 H),0.65 (m, 2 H); MS m/z 439 (M+1).

EXAMPLE 74N-Butyl-3-[2-(butylamino)pyrimidin-4-yl]-2-{4-[(4-methoxybenzyl)-amino]phenyl}pyrazolo[1,5-a]pyridin-7-amine

In a similar manner as described above fromN-{4-[2-(4-aminophenyl)-7-(butylamino)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-butylamine(100 mg, 0.23 mmol), and p-methoxybenzaldehyde (42 μL, 0.35 mmol) waspreparedN-butyl-3-[2-(butylamino)pyrimidin-4-yl]-2-{4-[(4-methoxybenzyl)amino]phenyl}pyrazolo[1,5-a]pyridin-7-amine(113 mg, 94%) as a pale yellow foam. ¹H NMR (CDCl₃): δ 7.92 (broad, 1H), 7.79 (d, 1 H), 7.46 (d, 2 H), 7.34–7.29 (m, 3 H), 6.91 (d, 2 H),6.71 (d, 2 H), 6.44 (d, 1 H), 6.07 (t, 1 H), 6.01 (d, 1 H), 4.33 (d, 2H), 4.16 (t, 1 H), 3.83 (s, 3 H), 3.53 (q, 2 H), 3.38 (q, 2 H),1.80–1.45 (m, 8 H), 0.99 (t, 6 H); MS m/z 550 (M+1).

EXAMPLE 75N-Butyl-3-[2-(butylamino)pyrimidin-4-yl]-2-(4-morpholin-4-ylphenyl)pyrazolo[1,5-a]pyridin-7-amine

In a similar manner as described above fromN-{4-[2-(4-bromophenyl)-7-(butylamino)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-butylamine(100 mg, 0.20 mmol) was preparedN-butyl-3-[2-(butylamino)pyrimidin-4-yl]-2-(4-morpholin-4-ylphenyl)pyrazolo[1,5-a]pyridin-7-amine(23.5 mg, 23%) as a yellow solid. ¹H NMR (CDCl₃): δ 7.88 (broad, 1 H),7.74 (d, 1 H), 7.51 (d, 2 H), 7.28 (t, 1 H), 6.94 (d, 2 H), 6.34 (d, 1H), 6.02 (t, 1 H), 5.97 (d, 1 H), 3.86 (m, 4 H), 3.47 (q, 2 H), 3.33 (q,2 H), 3.21 (m, 4 H), 1.74–1.41 (m, 8 H), 0.94 (t, 6 H); MS m/z 500(M+1).

EXAMPLE 762-(3-Bromophenyl)-N-cyclopentyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine

In a similar manner as described in Example 46 from(2E)-1-[2-(3-bromophenyl)-7-(cyclopentylamino)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one(0.38 g, 0.84 mmol),2-(3-bromophenyl)-N-cyclopentyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine(0.19 g, 47%) was obtained as a yellow crystalline solid. ¹H NMR(DMSO-d₆): δ 8.01 (d, 1H), 7.84 (d, 1H), 7.81 (s, 1H), 7.67 (d, 1H),7.59 (d, 1H), 7.44–7.35 (m, 2H), 7.28 (s, 1H), 6.63 (d, 1H), 6.21 (m,2H), 4.00 (m, 1H), 2.68 (m, 1H), 2.07–2.03 (m, 2H), 1.74–1.56 (m, 6H),0.67–0.63 (m, 2H), 0.49–0.46 (m, 2H); MS m/z 489 (M+1).

EXAMPLE 772-(3-Bromophenyl)-3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-cyclopropylpyrazolo[1,5-a]pyridin-7-amine

a) 2-(3-Bromophenyl)-7-chloropyrazolo[1,5-a]pyridine-3-carbaldehyde

A solution of N,N-Dimethylformamide (150 mL) and2-(3-bromophenyl)-7-chloropyrazolo[1,5-a]pyridine (10.3 g, 33 mmol) wascooled to 0° C. and treated with phosphorous oxychloride (4.7 mL, 50mmol). After the addition was complete, the mixture was warmed to roomtemperature and the resultant solution was stirred over the weekend.Water was added, followed by dichloromethane. The aqueous layer wasextracted with dichloromethane. The combined organics were washed withbrine, dried over magnesium sulfate, filtered and concentrated. Theresidue was washed with diethyl ether and hexanes to give2-(3-bromophenyl)-7-chloropyrazolo[1,5-a]pyridine-3-carbaldehyde (10.6g, 96%) as a fluffy white solid. ¹H NMR (DMSO-d₆): δ 10.09 (s, 1 H),8.37 (d, 1 H), 8.11 (d, 1H), 7.95 (d, 1H), 7.80 (m, 2 H), 7.65 (d, 1 H),7.55 (m, 1 H).

b)1-[2-(3-Bromophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol

In a similar manner as described in Example 46 from2-(3-bromophenyl)-7-chloropyrazolo[1,5-a]pyridine-3-carbaldehyde (1.0 g,2.9 mmol) and ethynylmagnesium bromide (6.4 mL, 0.5 M intetrahydrofuran, 3.2 mmol) at 0 ° C., was obtained1-[2-(3-bromophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol(0.68 g, 68%) as a white solid. ¹H NMR (DMSO-d₆): δ 8.04 (m, 2 H), 7.87(d, 1 H), 7.67 (d, 1 H), 7.49 (t, 1 H), 7.38–7.29 (m, 2 H), 6.27 (bs, 1H), 5.69 (s, 1 H), 3.49 (d, 1 H).

c)1-[2-(3-Bromophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one

In a similar manner as described in Example 46 from1-[2-(3-bromophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol(1.0 g, 2.8 mmol) was obtained1-[2-(3-bromophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one(0.45 g, 45%) as a yellow solid. ¹H NMR (DMSO-d₆): δ 8.41 (dd, 1 H),7.88–7.62 (m, 5 H), 7.46 (m, 1 H), 4.65 (s, 1 H).

d)4-[2-(3-Bromophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine

In a similar manner as described in Example 46 from1-[2-(3-bromophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one(1.0 g, 2.8 mmol), N-cyclopentylguanidine hydrochloride and sodiumethoxide (4.1 mL, 21 wt % in ethanol, 3.6 mmol) at room temperature wasobtained4-[2-(3-bromophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(0.60 g, 46%) as a yellow crystalline solid. MS m/z 469 (M+1).

e)2-(3-Bromophenyl)-3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-cyclopropylpyrazolo[1,5-a]pyridin-7-amine

In a similar manner as described in Example 1 from4-[2-(3-bromophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(0.1 g, 0.21 mmol) and cyclopropylamine was obtained3-[2-(butylamino)-4-pyrimidinyl]-N-cyclopropyl-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-7-amine2-(3-bromophenyl)-3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-cyclopropylpyrazolo[1,5-a]pyridin-7-amine(0.02 g mg, 24%) as a yellow crystalline solid. ¹H NMR (CDCl₃): δ 8.08(d, 1 H), 7.89 (s, 1 H), 7.80 (d, 1 H), 7.58 (m, 2 H), 7.36 (m, 2 H),6.43 (d, 1 H), 6.35 (m, 2 H), 5.08 (d, 1H), 4.34 (m, 1 H), 2.72 (m, 1H), 2.12 (m, 2 H), 1.79–1.55 (m, 6 H), 0.93 (m, 2 H), 0.81 (m, 2 H); MSm/z 489 (M+1).

EXAMPLE 782-(3-Bromophenyl)-N-cyclopropyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine

a)4-[2-(3-Bromophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl-2-pyrimidinamine

In a similar manner as described in Example 46 from1-[2-(3-bromophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one(0.45 g, 1.25 mmol), N-cyclopropylguanidine sulfate and sodium ethoxide(0.61 mL, 21 wt % in ethanol, 1.6 mmol) at room temperature was obtained4-[2-(3-bromophenyl)-7-chloropyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl-2-pyrimidinamine(0.21 g, 39%) as a pale yellow solid. ¹H NMR (CDCl₃): δ 8.57 (d, 1 H),8.12 (d, 1 H), 7.86 (t, 1 H), 7.57 (m, 2 H), 7.28 (m, 2 H), 7.06 (d, 1H), 6.37 (d, 1 H), 5.38 (bs, 1 H), 2.84 (m, 1 H), 0.88 (m, 2 H), 0.63(m, 2 H); MS m/z 440 (M+1).

b)2-(3-Bromophenyl)-N-cyclopropyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine

In a similar manner as described in Example 46 from4-[2-(3-bromophenyl)-7-chloropyrazolo[1.5-a]pyridin-3-yl]-N-cyclopropyl-2-pyrimidinamine(0.2 g, 0.45 mmol) and cyclopropylamine was obtained2-(3-bromophenyl)-N-cyclopropyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine(0.04 g, 21%) as a yellow crystalline solid. ¹H NMR (CDCl₃): δ 8.07 (d,1 H), 7.90 (d, 1 H), 7.85 (t, 1 H), 7.55 (m, 2 H), 7.36–7.27 (m, 2 H),6.38 (m, 2 H), 6.30 (s, 1 H), 5.30 (s, 1H), 2.80 (m, 1 H), 2.68 (m, 1H), 0.89–0.60 (m, 8 H); MS m/z 461 (M+1).

EXAMPLE 79 MethylN-[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]glycinate

In a similar manner as described for above examples the title compoundwas prepared as a tan solid. ¹H NMR (CDCl₃): δ 8.00 (d, 1 H), 7.82 (d, 1H), 7.59 (d, 2 H), 7.27 (m, 1 H), 6.96 (d, 2 H), 6.58 (t, 1 H), 6.34 (d,1 H), 5.89 (d, 1 H), 5.10 (d, 1 H), 4.35 (m, 1 H), 6.16 (d, 2 H), 3.86(s, 3 H), 3.80 (s, 3 H), 2.07 (m, 2 H), 1.75–1.51 (m, 6 H); MS m/z 473(M+1).

EXAMPLE 80 5-[(3aS,4S,6aR)-2-Oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl]-N-(4-{7-(butylamino)-3-[2-(butylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-2-yl}phenyl)pentanamide

To a cold (0° C.) solution of thionyl chloride (1 mL) was added solidd-(+)-biotin (100 mg, 0.41 mmol). The resulting mixture was warmed toroom temperature and stirred for 1 hour. The excess thionyl chloride andother volatiles were removed under vacuum (<0.1 mm Hg) resulting in asolid residue. To this residue at 0° C. was added N,N-dimethylformamide(3 mL) followed by2-(4-aminophenyl)-N-butyl-3-[2-(butylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-amine(70 mg, 0.16 mmol) in 2 mL of N,N-dimethylformamide. The resultantsolution was stirred at room temperature for 1 hour at which time thereaction appeared to be complete by analytical methods. The solution wasstirred an additional 72 hours. Ethyl acetate and saturated aqueoussodium bicarbonate were added and the layers separated. The organiclayer was washed with brine. The aqueous layer was extracted with ethylacetate and the combined organics were dried over sodium sulfate.Filtration and concentration followed by flash chromatography (8%methanol in dichloromethane) provided5-[(3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl]-N-(4-{7-(butylamino)-3-[2-(butylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-2-yl}phenyl)pentanamide(30 mg, 28%) as a yellow solid. ¹H NMR (DMSO-d₆): δ 10.00 (s, 1 H), 7.90(d, 1 H), 7.66 (m, 3 H), 7.46 (d, 2 H), 7.29 (t, 1 H), 6.99–6.94 (m, 2H), 6.40 (s, 1 H), 6.32 (s, 1 H), 6.11–6.09 (m, 2 H), 6.25 (m, 1 H),4.09 (m, 1 H), 3.47–3.06 (m, 4 H), 2.77 (m, 1 H), 2.53 (m, 1 H), 2.44(m, 1 H), 2.97 (m, 2 H), 1.62–1.27 (m, 14 H), 0.89–0.83 (m, 6 H); MS m/z656 (M+1).

EXAMPLE 81N-[3-[2-(Cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)-pyrazolo[1,5-a]pyridin-7-yl]butane-1,4-diamine

In a similar manner as described for above examples the title compoundwas prepared as a yellow solid. ¹H NMR (CDCl₃): δ 7.99 (d, 1 H), 7.77(d, 1 H), 7.58 (d, 2 H), 7.30 (m, 1 H), 6,97 (d, 2 H), 6.34 (d, 1 H),6.17 (m, 1 H), 5.98 (d, 1 H), 5.27 (m, 1 H), 4.82 (broad, 2 H), 4.36 (m,1 H), 3.87 (s, 3 H), 3.38 (m, 2 H), 2.83–2.78 (m, 2 H), 2.09 (m 2 H),1.83–1.52 (m, 10 H); MS m/z 472 (M+1).

EXAMPLE 825-[(3aS,4S,6aR)-2-Oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl]-N-(4-{[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl)pentanamide

To a cold (0° C.) solution ofN-[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]butane-1,4-diamine(33 mg, 0.07 mmol) in N,N-dimethylformamide (3 mL) was addedtriethylamine (0.03 mL, 0.21 mmol) and d-biotin-N-hydroxysuccinimideester (27 mg, 0.08 mmol). The resultant mixture was warmed to roomtemperature and stirred for 30 minutes. A subsequent 5 mg ofd-biotin-N-hydroxysuccinimide ester was added and the mixture wasstirred an additional 30 minutes. Water was added and the layers wereseparated. The organic layer was washed with saturated aqueous sodiumbicarbonate and then brine. The aqueous layer was extracted withdichloromethane and the combined organics were dried over sodiumsulfate. Filtration and concentration followed by flash chromatography(5% to 8% methanol in dichloromethane) provided5-[(3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl]-N-(4-{[3-[2-(cyclopentylamino)-pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl)-pentanamide(25 mg, 51%) as a yellow solid. ¹H NMR (CDCl₃): δ 7.98 (d, 1 H), 7.80(d, 1 H), 7.58 (d, 2 H), 7.32 (m, 1 H), 7.00 (d, 2 H), 6.60 (s,1 H),6.39 (m, 1 H), 6.33 (d, 1 H), 6.18 (m, 1 H), 6.02 (m, 1 H), 5.72 (s, 1H), 5.62 (broad, 1 H), 4.44–4.31 (m, 2 H), 4.19 (m, 1 H), 3.89 (s, 3 H),3.39 (m, 2 H), 3.28 (m, 2 H), 3.06 (m, 1 H), 2.95 (m, 2 H), 2.77 (dd, 1H), 2.58 (d, 1 H), 2.20–2.05 (m, 4 H), 1.82–1.54 (m, 12 H), 1.39 (m, 2H); MS m/z 698 (M+1).

EXAMPLE 833-[2-(Cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo-[1,5-a]pyridin-7-amine

To a solution of4-[7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentylpyrimidin-2-amine(100 mg, 0.24 mmol) in 1-methyl-2-pyrrolidinone (3 mL) was added sodiumazide (200 mg, 3.1 mmol). The resulting suspension was heated at 80° C.until the reaction was judged complete by thin layer chromatography. Themixture was cooled to room temperature and water and ether were added.The organic layer was washed with brine. The aqueous layer was extractedwith ether and the combined organics were dried over sodium sulfate.Filtration and concentration followed by flash chromatography (2:1 to1:1 hexanes-ethyl acetate) provided3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine(50 mg, 52%) as a yellow powder. ¹H NMR (CDCl₃): δ 8.03 (d, 1 H), 7.87(d, 1 H), 7.62 (d, 2 H), 7.27 (m, 1 H), 7.01 (d, 2 H), 6.37 (d, 1 H),6.17 (d, 1 H), 5.39 (s, 2 H), 5.19 (d, 1 H), 4.39 (m, 1 H), 3.90 (s, 3H), 2.10 (m, 2 H), 1.82–1.54 (m, 6 H); MS m/z 401(M+1).

EXAMPLE 84N,N″-di-tert-butoxycarbonyl-N′-(4-{[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl)guanidine

To a cold (0° C.) solution ofN-[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]butane-1,4-diamine(43 mg, 0.09 mmol) in dichloromethane (3 mL) was added triethylamine(0.03 mL, 0.18 mmol) and N,N-di-boc-N′-triflylguanidine (see Goodman et.al. Journal of Organic Chemistry 1998, 63, 3804). The resultant solutionwas warmed to room temperature and stirred overnight. Saturated aqueoussodium bicarbonate and ether were added. The organic layer was washedwith brine. The aqueous layer was extracted with ether and the combinedorganics were dried over sodium sulfate. Filtration and concentrationfollowed by flash chromatography (2:1 to 1:1 hexanes-ethyl acetate)providedN,N″-di-tert-butoxycarbonyl-N′-(4-{[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl)guanidine(42 mg, 65%). ¹H NMR (CDCl₃): δ 11.54 (s, 1 H), 8.40 (m, 1 H), 8.02 (m,1 H), 7.80 (d, 1 H), 7.61 (d, 2 H), 7.33 (m, 1 H), 7.01 (d, 2 H), 6.36(d, 1 H), 6.11 (m, 1 H), 6.02 (d, 1 H), 5.12 (m, 1 H), 4.39 (m, 1 H),3.89 (s, 3 H), 3.56–3.42 (m, 4 H), 2.14–2.06 (m, 2 H), 1.90–1.50 (m, 10H), 1.53 (s, 9 H), 1.52 (s, 9 H); MS m/z 714 (M+1).

EXAMPLE 85N-(4-{[3-[2-(Cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl)guanidine

To a solution ofN,N″-di-tert-butoxycarbonyl-N′-(4-{[3-[2-(cyclopentylamino)-pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl)-guanidine(42 mg, 0.06 mmol) in dichloromethane (8 mL) was added trifluoroaceticacid (2 mL). The resultant solution was stirred for 8 hours and thenconcentrated in vacuo. The residue was dissolved in dichloromethane andsaturated aqueous sodium bicarbonate was added. The organic layer waswashed with brine. The aqueous layer was extracted with dichloromethaneand the combined organics were dried over sodium sulfate. Filtration andconcentration providedN-(4-{[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl)guanidine(10 mg, 33%) as a yellow solid. MS m/z 514 (M+1).

EXAMPLE 86N-(4-{[3-[2-(Cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl)methanesulfonamide

To a cold (0° C.) solution ofN-[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]butane-1,4-diamine(21 mg, 0.04 mmol) in dichloromethane (3 mL) was added triethylamine(0.02 mL, 0.13 mmol) and methanesulfonyl chloride (0.05 mL). Theresultant solution was stirred at 0° C. for 1 hour and saturated aqueoussodium bicarbonate was added. The organic layer was washed with brine.The aqueous layer was extracted with dichloromethane and the combinedorganics were dried over sodium sulfate. Filtration and concentrationfollowed by flash chromatography (5% methanol in dichloromethane)providedN-(4-{[3-[2-(Cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl)methanesulfonamide(25 mg, 99%) a yellow solid. ¹H NMR (CDCl₃): δ 8.01 (d, 1 H), 7.79 (d, 1H), 7.59 (d, 2 H), 7.32 (m, 1 H), 7.01 (d, 2 H), 6.34 (d, 1 H), 6.13 (m,1 H), 6.00 (d, 1 H), 5.34 (d, 1 H), 5.02 (m, 1 H), 4.38 (m, 1 H), 3.90(s, 3 H), 3.38 (m, 2 H), 3.13 (m, 2 H), 2.94 (s, 3 H), 2.14–2.06 (m, 2H), 1.82–1.54 (m, 10 H); MS m/z 550 (M+1).

EXAMPLE 87N-{[(4-{[3-[2-(Cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl)amino]carbonyl}-4-methylbenzenesulfonamide

To a cold (0° C.) solution ofN-[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]butane-1,4-diamine(28 mg, 0.05 mmol) in dichloromethane (5 mL) was added triethylamine(0.1 mL) and p-tolylsulfonyl isocyanate (0.012 mL, 0.08 mmol). Theresultant solution was stirred at 0° C. for 1 hour and saturated aqueoussodium bicarbonate was added. The organic layer was washed with brine.The aqueous layer was extracted with dichloromethane and the combinedorganics were dried over sodium sulfate. Filtration and concentrationfollowed by flash chromatography (5% methanol in dichloromethane) andrecrystallization from dichloromethane-ether providedN-{[(4-{[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl)amino]carbonyl}-4-methylbenzenesulfonamide(14 mg, 35%) as a yellow solid. ¹H NMR (CDCl₃): δ 8.03 (m, 1 H),7.84–7.76 (m, 3 H), 7.58 (d, 2 H), 7.36–7.26 (m, 5 H), 7.01 (d, 2 H),6.66 (m, 1 H), 6.34 (m 1 H), 6.04 (m, 2 H), 4.36 (m, 1 H), 3.91 (s, 3H), 3.38–3.30 (m, 4 H), 2.36 (s, 3 H), 2.07 (m, 2 H), 1.82–1.54 (m, 10H); MS m/z 669 (M+1).

EXAMPLE 884-[(4-{[3-[2-(Cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl)amino]-4-oxobutanoicacid

To a solution ofN-[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]butane-1,4-diamine(25 mg, 0.05 mmol) in dichloromethane (4 mL) was added succinicanhydride (6 mg, 0.6 mmol). The resultant solution was stirred overnightand then ether was added. The precipitated solids were recovered byfiltration to give4-[(4-{[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl)amino]-4-oxobutanoicacid (31 mg, 99%) as a white solid. ¹H NMR (CDCl₃/CD₃OD): δ 7.71 (m, 2H), 7.47 (d, 2 H), 7.32 (m, 1 H), 6.97 (d, 2 H), 6.15 (d, 1 H), 6.04 (d,1 H), 4.30 (m, 1 H), 3.88 (s, 3 H), 3.38–3.27 (m, 4 H), 2.62 (m, 2 H),2.45 (m, 2 H), 2.10–2.00 (m, 2 H), 1.84–1.55 (m, 10 H); MS m/z 572(M+1).

EXAMPLE 89 Diethyl4-{[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butylamidophosphate

To a cold (0° C.) solution ofN-[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]butane-1,4-diamine(21 mg, 0.04 mmol) in dichloromethane (3 mL) was added triethylamine(0.1 mL), and diethyl chlorophosphate (0.1 mL of a stock solutionprepared from 0.1 mL of diethyl chlorophosphate in 3 mL ofdichloromethane). The resultant solution was stirred for 3 hours at 0°C. and then quenched by the addition of saturated aqueous sodiumbicarbonate. The organic layer was washed with brine. The aqueous layerwas extracted with dichloromethane and the combined organics were driedover sodium sulfate. Filtration and concentration followed by flashchromatography (5% methanol in dichloromethane) provided diethyl4-{[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butylamidophosphate(22 mg, 81%) as a yellow solid. ¹H NMR (CDCl₃): δ 7.98 (d, 1 H), 7.76(d, 1 H), 7.55 (d, 2 H), 7.28 (m, 1 H), 6.96 (d, 2 H), 6.31 (d, 1 H),6.06 (m, 1 H), 5.97 (d, 1 H), 5.11 (d, 1 H), 4.34 (m, 1 H), 4.09–3.98(m, 4 H), 3.86 (s, 3 H), 3.37 (m, 2 H), 2.95 (m, 2 H), 2.64 (m, 1 H),2.11–1.48 (m, 12 H), 1.31–1.27 (m, 6 H); MS m/z 608 (M+1).

EXAMPLE 904-{[3-[2-(Cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)-pyrazolo[1,5-a]pyridin-7-yl]amino}butan-1-ol

In a similar manner as described for above examples the title compoundwas prepared as a yellow foam. ¹H NMR (CDCl₃): δ 7.98 (d, 1 H), 7.75 (d,1 H), 7.56 (d, 2 H), 7.29 (m, 1 H), 6.97 (d, 2 H), 6.31 (d, 1 H), 6.12(m, 1 H), 5.99 (d, 1 H), 5.04 (d, 1 H), 4.35 (m, 1 H), 3.86 (s, 3 H),3.71 (m, 2 H), 3.42 (m, 2 H), 2.07 (m, 2 H), 1.86 (m, 2 H), 1.76–1.49(m, 8 H); MS m/z 473 (M+1).

EXAMPLE 91 Dibenzyl4-{[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butylphosphate

To a room temperature solution of4-{[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butan-1-ol(22 mg, 0.05 mmol) in dichloromethane (5 mL) was added 1-H-tetrazole (7mg, 0.1 mmol) and dibenzyl N,N-diisopropylphosphoramidate (0.32 mL of astock solution prepared from 0.2 mL of dibenzylN,N-diisopropylphosphoramidate in 3.2 mL of dichloromethane). Theresultant solution was stirred at room temperature for 1 hour and thencooled to 0° C. lodobenzene diacetate (16.5 mg, 0.05 mmol) was added andthe mixture was stirred for 20 minutes. Saturated aqueous sodiumthiosulfate and saturated aqueous sodium bicarbonate were added and thelayers separated. The organic layer was washed with brine. The aqueouslayer was extracted with dichloromethane and the combined organics weredried over sodium sulfate. Filtration and concentration followed byflash chromatography (1:4 hexanes-ethyl acetate) provided dibenzyl4-{[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butylphosphate (18 mg, 53%). ¹H NMR (CDCl₃): δ 8.03 (d, 1 H), 7.81 (d, 1 H),7.61 (d, 2 H), 7.38–7.32 (m, 11 H), 7.01 (d, 2 H), 6.36 (d, 1 H), 6.06(m, 1 H), 5.98 (d, 1 H), 5.13–5.01 (m, 5 H), 4.40 (m, 1 H), 4.05 (m, 2H), 3.91 (s, 3 H), 3.37 (m, 2 H), 2.16–1.54 (m, 12 H); MS m/z 733 (M+1).

EXAMPLE 924-{[3-[2-(Cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxy-phenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butylphosphate diammonium salt

A solution of dibenzyl4-{[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butylphosphate (55 mg, 0.07 mmol) in methanol (10 mL) was treated with acatalytic amount of palladium on carbon. This mixture was placed under ahydrogen atmosphere (48 psi) for 14 hours. The catalyst was removed byfiltration through Celite with ammonia in ethanol as eluent. Thefiltrate was concentrated in vacuo and the residue was triturated withmethanol/ether to provide4-{[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butylphosphate as its diammonium salt. ¹H NMR (DMSO-d₆): δ 10.89 (broad, 2H), 7.93 (d, 1 H), 7.77 (broad, 1 H), 7.50 (d, 2 H), 7.34 (t, 1 H),7.09–7.01 (m, 4 H), 6.16 (m, 2 H), 4.15 (m, 1 H), 3.84 (m, 2 H), 3.80(s, 3 H), 3.36 (m, 2 H), 1.92–1.50 (m, 12 H); HRMS m/z 553.2357 (calcdfor C₂₇H₃₃N₆O₅P free base 552.2250) (M+1).

EXAMPLE 932-(3-Azidophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-amine

This reaction was performed in a dark environment. To a cold (0–5° C.)solution of2-(3-aminophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-amine(46 mg, 0.10 mmol) in acetic acid (3 mL) was added sodium nitrite (0.31mL of a 25 mg/mL aqueous stock solution, 7.7 mg, 0.11 mmol). The mixtureturned dark and was stirred for 20 minutes at 0° C. Sodium azide wasthen added and the mixture was stirred for 20 minutes, allowed to warmto room temperature and stirred for an additional 10 minutes. Ether wasadded and the mixture was neutralized with sodium bicarbonate. Aqueousworkup was followed by drying over sodium sulfate. Filtration andconcentration followed by flash chromatography (4:1 to 2:1 hexanes-ethylacetate) provided2-(3-azidophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-amine(25 mg, 52%) as a yellow solid. ¹H NMR (CDCl₃): δ 8.05 (d, 1 H), 7.75(d, 1 H), 7.45–7.42 (m, 3 H), 7.36 (t, 1 H), 7.13 (m, 1 H), 6.33 (d, 1H), 6.10–6.03 (m, 2 H), 5.10 (d, 1 H), 4.36 (m, 1 H), 4.05 (m, 1 H),2.20–1.54 (m, 16 H); MS m/z 480 (M+1); IR 2109 cm⁻¹.

EXAMPLE 943-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)-N-[2-oxo-2-(1-pyrrolidinyl)ethyl]pyrazolo[1,5-a]pyridin-7-amine

In a similar manner as described for above examples the title compoundwas prepared as a yellow solid. R_(f) 0.15 (1:2 hexanes:ethyl acetate);¹H NMR (CDCl₃): δ 8.02 (d, 1H), 7.79 (d, 1H), 7.65 (d, 2H), 7.28 (m,1H), 7.07 (t, 1H), 6.97 (d, 2H), 6.40 (d, 1H), 5.91 (d, 1H), 5.11 (d,1H), 4.38 (m, 1H), 4.06 (d, 2H), 3.88 (s, 3H), 3.59 (t, 2H), 3.49 (t,2H), 2.13–2.01 (m, 4H), 1.92 (m, 2H), 1.82–1.51 (m, 6H); MS m/z 512(M+1).

EXAMPLE 95N-(2-{[3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxy-phenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}ethyl)methanesulfonamide

In a similar manner as described for above examples the title compoundwas prepared as a yellow solid. R_(f) 0.33 (39:1dichloromethane:methanol); ¹H NMR (CDCl₃): δ 7.82 (br, 1H), 7.73 (d,1H), 7.46 (d, 2H), 7.27 (m, 1H), 6.94 (d, 2H), 6.25 (t, 1H), 6.12–6.08(m, 2H), 5.50 (br, 1H), 4.30 (m, 1H), 3.88 (s, 3H), 3.58 (m, 2H), 3.38(m, 2H), 2.95 (s, 3H), 2.06 (m, 2H), 1.81–1.56 (m, 6H); MS m/z 522(M+1).

EXAMPLE 96N′-[3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]-1,2-ethanediamine

In a similar manner as described for above examples the title compoundwas prepared as a light yellow solid. ¹H NMR (CDCl₃): δ 8.01 (d, 1H),7.80 (d, 1H), 7.59 (d, 2H), 7.32 (d, 1H), 6.99 (d, 2H), 6.35–6.30 (m,2H), 6.03 (d, 1H), 5.11 (d, 1H), 4.37 (m, 1H), 3.87 (s, 3H), 3.45 (m,2H), 3.07 (t, 2H), 2.09 (m, 2H), 1.78–1.44 (m, 6H); MS m/z 444 (M+1).

EXAMPLE 97N-Cyclopentyl-4-[2-(3-fluorophenyl)-7-(4-morpholinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

In a similar manner as described for above examples the title compoundwas prepared as a pale yellow solid. R_(f) 0.47 (99:1dichloromethane:methanol); ¹H NMR (CDCl₃) δ 8.11–8.09 (m, 2H), 7.49–7.30(m, 4H), 7.15 (t, 1 H), 6.40–6.35 (m, 2H), 5.28 (d, 1H), 4.36 (m, 1H),4.03 (m, 4H), 3.52 (m, 4H), 2.10 (m, 2H), 1.81–1.50 (m, 6H); MS m/z 459(M+1). Anal. Calcd for C₂₆H₂₇FN₆O: C, 68.10; H, 5.93; N, 18.33. Found:C, 68.07; H, 6.00; N, 18.18.

EXAMPLE 98N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-7-amine

In a similar manner as described for above examples the title compoundwas prepared as a light yellow solid. R_(f) 0.22 (4:1 hexanes:ethylacetate); ¹H NMR (300 MHz, CDCl₃) δ 8.06–8.02 (m, 2H), 7.84 (d, 1H),7.71–7.67 (m, 2H), 7.55 (t, 1H), 7.34 (t, 1H), 6.32 (d, 1H), 6.07 (d,1H), 6.03 (d, 1H), 5.08 (d, 1H), 4.28 (m, 1H), 4.03 (m, 1H), 2.17 (m,2H), 2.04 (m, 2H), 1.86–1.51 (m, 12H); MS m/z 507 (M+1).

EXAMPLE 992-(3-Chlorophenyl)-N-cyclopropyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine

In a similar manner as described for above examples the title compoundwas prepared as a yellowish-orange solid. ¹H NMR (CDCl₃): δ 8.07 (d, 1H)7.92 (d, 1H), 7.69 (s, 1H), 7.50 (d, 1H), 7.42–7.34 (m, 3H), 6.41 (d,1H), 6.37 (d, 1H), 6.30 (s, 1H), 5.35 (s, 1H), 2.84 (m, 1H), 2.68 (m,1H), 0.90–0.82 (m, 4H), 0.76 (m, 2H), 0.61 (m, 2H); MS m/z 417 (M+1).

EXAMPLE 1002-(3-Chlorophenyl)-N-cyclopentyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine

In a similar manner as described for above examples the title compoundwas prepared as a yellow solid. R_(f) 0.18 (4:1 hexanes:ethyl acetate);¹H NMR (CDCl₃): δ 8.07 (d, 1H), 7.85 (d, 1H), 7.71 (s, 1H), 7.52 (d,1H), 7.42–7.27 (m, 3H), 6.36 (d, 1H), 6.03 (d, 1H), 6.00 (d, 1H), 5.56(s, 1H), 3.99 (m, 1H), 2.81 (m, 1H), 2.13 (m, 2H), 1.82–1.65 (m, 6H),0.82 (m, 2H), 0.59 (m, 2H); MS m/z 445 (M+1).

EXAMPLE 1012-(3-Chlorophenyl)-3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-cyclopropylpyrazolo[1,5-a]pyridin-7-amine

In a similar manner as described for above examples the title compoundwas prepared as a yellow solid. R_(f) 0.26 (4:1 hexanes:ethyl acetate);¹H NMR (CDCl₃) δ 8.03 (d, 1H), 7.76 (d, 1H), 7.68 (s, 1H), 7.49 (d, 1H),7.41–7.33 (m, 3H), 6.40 (d, 1H), 6.32–6.30 (m, 2H), 5.10 (d, 1H), 4.31(m, 1H), 2.67 (m, 1H), 2.05 (m, 2H), 1.78–1.50 (m, 6H), 0.89 (m, 2H),0.75 (m, 2H); MS m/z 445 (M+1). Anal. Calcd for C₂₅H₂₅ClN₆: C, 67.48; H,5.66; N. 18.89. Found: C, 67.48; H, 5.80; N. 18.62.

EXAMPLE 102N-Cyclopentyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]-2-(3-fluorophenyl)pyrazolo[1,5-a]pyridin-7-amine

In a similar manner as described for above examples the title compoundwas prepared as a yellow solid. R_(f) 0.19 (4:1 hexanes:ethyl acetate);¹H NMR (CDCl₃): δ 8.11 (d, 1H), 7.90 (d, 1H), 7.48–7.30 (m, 4H), 7.18(t, 1H), 6.40 (d, 1H), 6.09 (d, 1H), 6.04 (d, 1H), 5.41 (s, 1H), 4.05(m, 1H), 2.88 (m, 1H), 2.18 (m, 2H), 1.88–1.69 (m, 6H), 0.89 (m, 2H),0.65 (m, 2H); MS m/z 429 (M+1).

EXAMPLE 1034-[2-(3-Chlorophenyl)-7-(4-morpholinyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine

In a similar manner as described for above examples the title compoundwas prepared as a white solid. R_(f) 0.49 (99:1dichloromethane:methanol); ¹H NMR (DMSO-d₆): δ 8.06 (d, 1H), 7.63 (s,1H), 7.54–7.42 (m, 5H), 7.10 (d, 1H), 6.55 (d, 1H), 6.23 (br, 1H), 4.10(br, 1H), 3.83 (m, 4H), 3.43 (m, 4H), 1.85 (m, 2H), 1.67 (m, 2H),1.53–1.45 (m, 4H); MS m/z 475 (M+1). Anal. Calcd for C₂₆H₂₇ClN₆O: C,65.75; H, 5.73; N. 17.69. Found: C, 65.67; H, 5.83; N. 17.64.

EXAMPLE 1042-(3-Chlorophenyl)-3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-(2-methoxyethyl)pyrazolo[1,5-a]pyridin-7-amine

In a similar manner as described for above examples the title compoundwas prepared as a yellow solid. R_(f) 0.41 (99:1dichloromethane:methanol); ¹H NMR (CDCl₃): δ 8.02 (d, 1H), 7.77–7.71 (m,2H), 7.53 (d, 1H), 7.44–7.32 (m, 3H), 6.34 (d, 1H), 6.30 (t, 1H), 6.08(d, 1H), 5.28 (br, 1H), 4.34 (m, 1H), 3.73 (t, 2H), 3.59 (m, 2H), 3.44(s, 3H), 2.07 (m, 2H), 1.80–1.52 (m, 6H); MS m/z 463 (M+1). Anal. Calcdfor C₂₅H₂₇ClN₆O: C, 64.86; H, 5.88; N. 18.15. Found: C, 65.03; H, 6.07;N, 18.05.

EXAMPLE 1053-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-cyclopropyl-2-(3-fluorophenyl)pyrazolo[1,5-a]pyridin-7-amine

In a similar manner as described for above examples the title compoundwas prepared as a yellow solid. R_(f) 0.76 (99:1dichloromethane:methanol); ¹H NMR (CDCl₃): δ 8.02 (d, 1H), 7.80 (d, 1H),7.45–7.37 (m, 4H), 7.15 (m, 1H), 6.42 (d, 1H), 6.34–6.32 (m, 2H), 5.20(br, 1H), 4.34 (m, 1H), 2.69 (m, 1H), 2.07 (m, 2H), 1.80–1.52 (m, 6H),0.90 (m, 2H), 0.77 (m, 2H); MS m/z 429 (M+1). Anal. Calcd for C₂₅H₂₅FN₆:C, 70.07; H, 5.88; N, 19.61. Found: C, 69.98; H, 5.98; N, 19.35.

EXAMPLE 1063-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(3-fluorophenyl)-N-(2-methoxyethyl)pyrazolo[1,5-a]pyridin-7-amine

In a similar manner as described for above examples the title compoundwas prepared as a yellow solid. R_(f) 0.33 (99:1dichloromethane:methanol); ¹H NMR (CDCl₃): δ 8.06 (d, 1H), 7.79 (d, 1H),7.49–7.30 (m, 4H), 7.17 (t, 1H), 6.37–6.30 (m, 2H), 6.09 (d, 1H), 5.18(br, 1H), 4.37 (m, 1H), 3.75 (m, 2H), 3.61 (m, 2H), 3.47 (s, 3H), 2.10(m, 2H), 1.81–1.52 (m, 6H); MS m/z 447 (M+1). Anal. Calcd forC₂₅H₂₇FN₆O: C, 67.25; H, 6.09; N, 18.82. Found: C, 67.20; H, 6.09; N,18.64.

EXAMPLE 107 Biological Activity

In the following example, “MEM” means Minimal Essential Media; “FBS”means Fetal Bovine Serum; “NP40” and “Igepal” are detergents; “MOI”means Multiplicity of Infection; “NaOH” means sodium hydroxide; “MgCl₂”means magnesium chloride; “dATP” means deoxyadenosine 5′ triphosphate;“dUTP” means deoxyuridine 5′ triphosphate; “dCTP” means dexoxycytidine5′ triphosphate; “dGTP” means deoxyguanosine 5′ triphosphate; “GuSCN”means Guanidinium thiocyanate; “EDTA” means ethylenediamine tetraaceticacid; “TE” means Tris-EDTA; “SCC” means sodium chloride/sodium citrate;“APE” means a solution of ammonia acetate, ammonia phosphate, EDTA;“PBS” means phosphate buffered saline; and “HRP” means horseradishperoxidase.

a) Tissue Culture and HSV Infection.

Vero 76 cells were maintained in MEM with Earle's salts, L-glutamine, 8%FBS (Hyclone, A-1111-L) and 100 units/mL Penicillin-100 μg/mLStreptomycin. For assay conditions, FBS was reduced to 2%. Cells areseeded into 96-well tissue culture plates at a density of 5×10⁴cells/well after being incubated for 45 min at 37° C. in the presence ofHSV-1 or HSV-2 (MOI=0.001). Test compounds are added to the wells andthe plates are incubated at 37° C. for 40–48 hours. Cell lysates areprepared as follows: media was removed and replaced with 150 μL/well 0.2N NaOH with 1% Igepal CA 630 or NP-40. Plates were incubated up to 14days at room temperature in a humidified chamber to prevent evaporation.

(b) Preparation of Detection DNA.

For the detection probe, a gel-purified, digoxigenin-labeled, 710-bp PCRfragment of the HSV UL-15 sequence was utilized. PCR conditions included0.5 μM primers, 180 μM dTTP, 20 μM dUTP-digoxigenin (Boehringer Mannheim1558706), 200 μM each of dATP, dCTP, and dGTP, 1×PCR Buffer II (PerkinElmer), 2.5 mM MgCl₂, 0.025 units/μL of AmpliTaq Gold polymerase (PerkinElmer), and 5 ng of gel-purified HSV DNA per 100 μL Extension conditionswere 10 min at 95° C., followed by 30 cycles of 95° C. for 1 min, 55° C.for 30 sec, and 72° C. for 2 min. The amplification was completed with a10-min incubation at 72° C. Primers were selected to amplify a 728 bpprobe spanning a section of the HSV1 UL15 open reading frame(nucleotides 249–977). Single-stranded transcripts were purified withPromega M13 Wizard kits. The final product was mixed 1:1 with a mixtureof 6 M GuSCN, 100 mM EDTA and 200 μg/mL herring sperm DNA and stored at4° C.

(c) Preparation of Capture Plates.

The capture DNA plasmid (HSV UL13 region in pUC) was linearized bycutting with Xba I, denatured for 15 min at 95° C. and dilutedimmediately into Reacti-Bind DNA Coating Solution (Pierce, 17250,diluted 1:1 with TE buffer, pH 8) at 1 ng/μL 75 μL/well were added toCorning (#3922 or 9690) white 96-well plates and incubated at roomtemperature for at least 4 hrs before washing twice with 300 μL/well0.2×SSC/0.05% Tween-20 (SSC/T buffer). The plates were then incubatedovernight at room temperature with 150 μL/well 0.2 N NaOH, 1% IGEPAL and10 μg/mL herring sperm DNA.

d) Hybridization.

Twenty-seven (27) μL of cell lysate was combined with 45 μL ofhybridization solution (final concentration: 3M GuSCN, 50 mM EDTA, 100μg/ml salmon sperm DNA, 5×Denhardt's solution, 0.25×APE, and 5 ng of thedigoxigenin-labeled detection probe). APE is 1.5 M NH₄-acetate, 0.15 MNH₄H₂ phosphate, and 5 mM EDTA adjusted to pH 6.0. Mineral oil (50 μL)was added to prevent evaporation. The hybridization plates wereincubated at 95° C. for 10 minutes to denature the DNA, then incubatedat 42° C. overnight. The wells were washed 6× with 300 μL/well SSC/Tbuffer then incubated with 75 μL/well anti-digoxigenin-HRP-conjugatedantibody (Boehringer Mannheim 1207733, 1:5000 in TE) for 30 min at roomtemperature. The wells were washed 6× with 300 μL/well with PBS/0.05%Tween-20 before 75 μL/well SuperSignal LBA substrate (Pierce) was added.The plates were incubated at room temperature for 30 minutes andchemiluminescence was measured in a Wallac Victor reader.

e) Results.

The following results were obtained for HSV-1.

Example No. IC₅₀ (μM) 1 0.3 2 0.6 3 5 4 1 5 2 6 5 7 0.15 8 3 9 3 10 0.911 0.3 12 2 13 1 15 1 16 1 17 1.5 18 9 19 0.5 20 16 21 15 22 0.6 23 2 240.9 25 0.2 26 0.6 27 1.5 28 5 29 3 30 0.8 31 2 32 0.6 33 0.8 34 0.6 35 236 3 37 3.0 38 0.3 39 0.5 40 2.5 41 3.5 42 1.4 43 0.5 44 1.8 45 22 460.2 48 >40 49 0.5 50 2.5 51 0.21 52 0.56 53 1.1 54 0.65 55 0.1 56 0.2 570.2 58 0.4 59 0.4 60 0.4 61 0.2 62 0.1 63 1.2 64 0.3 65 0.5 66 1.3 670.3 68 1.2 69 2.3 70 0.6 71 0.5 72 1.4 73 2.0 75 27 79 2.5 81 0.6 82 0.483 0.7 85 4 86 0.6 87 1 88 9 89 0.8 90 0.2 92 0.3 93 0.7 94 6.2 95 0.396 1.1 97 0.7 98 0.3 99 0.5 100 0.3 101 0.2 102 0.7 103 0.5 104 0.2 1050.6 106 0.2

The results demonstrate that the compounds of the present invention areuseful for the treatment and prophylaxis of herpes viral infections.

1. A compound of formula (I):

wherein: R¹ is selected from the group consisting of halo, —NR⁷R⁸, Ay,—NR⁷Ay, Het, —NHR¹⁰Het, —NHHet and —NHR¹⁰Ay; each R⁷ and R⁸ are the sameor different and are independently selected from the group consisting ofH, alkyl, cycloalkyl, alkenyl, cycloalkenyl, —R¹⁰cycloalkyl, —R¹⁰OR⁹,—NR⁹R¹¹, —R¹⁰NR⁹R¹¹, —R¹⁰C(O)R⁹, —C(O)R⁹, —C(O)R¹⁰Ay, —C(O)R¹⁰Het,—CO₂R⁹, —R¹⁰CO₂R⁹, —C(O)NR⁹R¹¹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(O)Ay, —R¹⁰C(O)Het,—C(S)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰NHC(O)R¹⁰Het,—R¹⁰NHC(O)R¹⁰CO₂R⁹, —R¹⁰NHC(NCO₂R⁹)NHCO₂R⁹, —R¹⁰NHC(O)NHSO₂R⁹,—R¹⁰NHC(O)NHSO₂Ay, —R¹⁰NHC(O)NHSO₂Het, —R¹⁰C(NH)NR⁹R¹¹, —C(NH)NR⁹R¹¹,—SO₂NR⁹R¹¹, —R¹⁰SO₂NR⁹R¹¹, —R¹⁰NHSO₂R⁹, —SO₂R¹⁰, —R¹⁰SO₂R¹⁰, —R¹⁰NHCOR⁹,—R¹⁰SO₂NHCOR⁹, —R¹⁰NHP(O)(OR⁹)₂, —R¹⁰OP(O)(OR⁹)₂ and —R¹⁰OP(O)(OR¹⁰Ay)₂;each R⁹ and R¹¹ are the same or different and are independently selectedfrom the group consisting of H, alkyl, cycloalkyl, —R¹⁰cycloalkyl,—R¹⁰OH, —R¹⁰(OR¹⁰)_(w) where w is 1–10, and —R¹⁰NR¹⁰R¹⁰; each R¹⁰ is thesame or different and is independently selected from the groupconsisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl and alkynyl; Ayis aryl; Het is a 5- or 6-membered heterocyclic or heteroaryl group; R²is selected from the group consisting of halo, alkyl, cycloalkyl,alkenyl, cycloalkenyl, —NR⁷R⁸, —OR⁷, —OAy, —S(O)_(n)R⁹, —S(O)_(n)Ay,—R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, Ay, Het, —NHHet, —NHR¹⁰Het, —OHet and —OR¹⁰Het; nis 0, 1 or 2; Y is N; R³ and R⁴ are the same or different and are eachindependently selected from the group consisting of H, halo, alkyl,cycloalkyl, alkenyl, Ay, —OR⁷, —OAy, —R¹⁰OR⁷, —R¹⁰OAy, —NR⁷R⁸, —NR⁷Ay,—R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —C(O)R⁷, —C(O)Ay, —CO₂R⁷, —CO₂Ay, —SO₂NHR⁹, Het,—NHHet and —NHR¹⁰Het; q is 0, 1, 2, 3, 4 or 5; and each R⁵ is the sameor different and is independently selected from the group consisting ofhalo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, —R¹⁰cycloalkyl,Ay, —NHR¹⁰Ay, Het, —NHHet, —NHR¹⁰Het, —OR⁷, —OAy, —OHet, —R¹⁰OR⁹,—NR⁷R⁸, —NR⁷Ay, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —C(O)R⁹, —CO₂R⁹,—R¹⁰CO₂R⁹, —C(O)NR⁷R⁸, —C(O)Ay, —C(O)NR⁷Ay, —C(O)Het, —C(O)NHR¹⁰Het—R¹⁰C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹,—C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —R¹⁰C(NH)NR⁹R¹¹, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay,—R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂R⁹, —S(O)_(n)R⁹, cyano, nitro andazido; or  two adjacent R⁵ groups together with the atoms to which theyare bonded form a C₅₋₆ cycloalkyl or aryl; wherein when q is 1 and R⁵ isin the para position, R⁵ is not halo; and or a pharmaceuticallyacceptable salt thereof.
 2. The compound according to claim 1 wherein R¹is selected from the group consisting of —NR⁷R⁸, Ay, —NR⁷Ay, Het,—NHR¹⁰Het, —NHHet and —NHR¹⁰Ay.
 3. The compound according to claim 1wherein R¹ is selected from the group consisting of —NR⁷R⁸ and Het. 4.The compound according to claim 1 wherein R² is selected from the groupconsisting of —NR⁷R⁸, —OR⁷, —OAy, —S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸,—R¹⁰NR⁷Ay, Ay, Het, —NHR¹⁰Het, —NHHet, —OHet and —OR¹⁰Het.
 5. Thecompound according to claim 1 wherein R² is selected from the groupconsisting of —NR⁷R⁸ and Het.
 6. The compound according to claim 1wherein R³ and R⁴ are the same or different and are each independentlyselected from the group consisting of H, halo, alkyl, —OR⁷, —R¹⁰OR⁷,—NR⁷R⁸, —R¹⁰NR⁷R⁸, —CO₂R⁷ and Ay.
 7. The compound according to claim 1wherein R³ and R⁴ are each H.
 8. The compound according to claim 1wherein q is 0 or
 1. 9. The compound according to claim 1 wherein eachR⁵ is the same or different and is independently selected from the groupconsisting of halo, alkyl, alkenyl, —OR⁷, —CO₂R⁹, —NR⁷R⁸, —C(O)NR⁷R⁸,Ay, —NHR¹⁰Ay, Het, —S(O)₂NR⁷R⁸, cyano, nitro and azido.
 10. The compoundaccording to claim 1 wherein each R⁵ is the same or different and isindependently selected from the group consisting of halo, alkyl, —OR⁷,—NR⁷R⁸ and cyano.
 11. A compound selected from the group consisting of:N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)-pyrazolo[1,5-a]pyridin-7-amine,N-Cyclopentyl-4-[2-(4-methoxyphenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine,4-[2-(4-Methoxyphenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine,4-{7-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo-[1,5-a]pyridin-2-yl}phenol,4-[3-[2-(Cyclopentylamino)-4-pyrimidinyl]-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenol,4-[3-(2-Amino-4-pyrimidinyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenol,2-[4-(Allyloxy)phenyl]-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo-[1,5-a]pyridin-7-amine,Ethyl(4-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]-pyrazolo[1,5-a]pyridin-2-yl}phenoxy)acetate,2-(4-Butoxyphenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-pyrazolo[1,5-a]pyridin-7-amine,N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-isobutoxyphenyl)pyrazolo-[1,5-a]pyridin-7-amine,N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[4-(cyclopropyl-methoxy)-phenyl]pyrazolo[1,5-a]pyridin-7-amine,2-[4-(Cyclobutylmethoxy)phenyl]-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine,N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-phenoxyphenyl)-pyrazolo[1,5-a]pyridin-7-amine,2-[1,1′-Biphenyl]-4-yl-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]pyrazolo-[1,5-a]pyridin-7-amine,N-{4-[2-(4-Aminophenyl)-7-(butylamino)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-butylamine,N-Butyl-3-[2-(butylamino)-4-pyrimidinyl]-2-[4-(cyclohexylamino)phenyl]-pyrazolo[1,5-a]pyridin-7-amine,N-Butyl-3-[2-(butylamino)-4-pyrimidinyl]-2-(4-isopropenylphenyl)-pyrazolo[1,5-a]pyridin-7-amine,2-(4-Anilinophenyl)-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine,2-(4-Anilinophenyl)-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]-N-phenylpyrazolo[1,5-a]pyridin-7-amine,2-{4-[Bis(cyclopropylmethyl)amino]phenyl}-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine,N-butyl-3-[2-(butylamino)-4-pyrimidinyl]-2-{4-[(cyclopropylmethyl)amino]phenyl}-pyrazolo[1,5-a]pyridin-7-amine,N-Butyl-3-[2-(butylamino)-4-pyrimidinyl]-2-[4-(dimethylamino)phenyl]-pyrazolo[1,5-a]pyridin-7-amine,2-(2-Bromophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine,2-(3-Bromophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine,4-[2-(3-Bromophenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine,N-[3-(2-Amino-4-pyrimidinyl)-2-(3-bromophenyl)pyrazolo[1,5-a]pyridin-7-yl]-N-cyclopentylamine,4-[2-(3-Bromophenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine,2-[1,1′-Biphenyl]-3-yl-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo-[1,5-a]pyridin-7-amine,4-[2-[1,1′-Biphenyl]-3-yl-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine,N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[3-(4-pyridinyl)phenyl]-pyrazolo[1,5-a]pyridin-7-amine,N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[3-(3-thienyl)phenyl]pyrazolo-[1,5-a]pyridin-7-amine,N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[3-(2-thienyl)-phenyl]pyrazolo[1,5-a]pyridin-7-amine,2-(3-Aminophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine,N-(3-{7-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenyl)acetamide,N-(3-{7-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]-pyrazolo[1,5-a]pyridin-2-yl}phenyl)methanesulfonamide,4-[2-(3-Aminophenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine,N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-phenylpyrazolo-[1,5-a]pyridin-7-amine,3-{7-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}benzonitrile,3-{7-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]-pyrazolo[1,5-a]pyridin-2-yl}benzamide,3-{7-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo-[1,5-a]pyridin-2-yl}benzoicacid,N-{4-[2-(3-Bromo-4-methoxyphenyl)-7-(cyclopentylamino)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-cyclopentylamine,2-(3-Bromo-4-chlorophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-pyrazolo[1,5-a]pyridin-7-amine,2-(3-Amino-4-chlorophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine,2-[4-(Benzylamino)phenyl]-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]-pyrazolo[1,5-a]pyridin-7-amine,N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-7-amine,4-[7-Chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-5,6-dimethyl-2-pyrimidinamine,N-cyclopentyl-3-[2-(cyclopentylamino)-5,6-dimethyl-4-pyrimidinyl]-2-(3-methylphenyl)pyrazolo[1,5-a]pyridin-7-amine,3-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-isopropyl-2-(3-methylphenyl)pyrazol[1,5-a]pyridin-7-amine,4-[7-Chloro-2-(3-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine,N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(3-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine,3-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-isopropyl-2-(3-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine,3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(3-methoxyphenyl)-N,N-dimethylpyrazolo[1,5-a]pyridin-7-amine,3-{7-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenol,N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[3-(cyclopropylmethoxy)phenyl]pyrazolo[1,5-a]pyridin-7-amine,N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(3-fluorophenyl)pyrazolo[1,5-a]pyridin-7-amine,2-(3-Chlorophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine,N-Cyclopentyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine,3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)-N-[2-(4-morpholinyl)ethyl]pyrazolo[1,5-a]pyridin-7-amine,3-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-cyclopropyl-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine,N-Cyclopentyl-4-[2-(4-methoxyphenyl)-7-(4-morpholinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine,3-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-(2-methoxyethyl)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine,N-Cyclopropyl-4-[2-(4-methoxyphenyl)-7-(4-morpholinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine,3-[2-(Cyclopropylamino)-4-pyrimidinyl]-N-(2-methoxyethyl)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine,3-[2-(Cyclopropylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)-N-[2-(4-morpholinyl)ethyl]pyrazolo[1,5-a]pyridin-7-amine,N-Cyclopropyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine,4-[3-[2-(Cyclopentylamino)-4-pyrimidinyl]-7-(cyclopropylamino)pyrazolo[1,5-a]pyridin-2-yl]phenol,4-{7-(Cyclopentylamino)-3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenol,4-{7-(Cyclopropylamino)-3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenol,3-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-cyclopropyl-2-[4-(cyclopropylmethoxy)phenyl]pyrazolo[1,5-a]pyridin-7-amine,2-[4-(Allyloxy)phenyl]-N-cyclopentyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine,N-Cyclopropyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]-2-[4-(cyclopropylmethoxy)phenyl]pyrazolo[1,5-a]pyridin-7-amine,2-[4-(Allyloxy)phenyl]-N-cyclopropyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine,N-Butyl-3-[2-(butylamino)pyrimidin-4-yl]-2-{4-[(4-methoxybenzyl)amino]phenyl}pyrazolo[1,5-a]pyridin-7-amine,N-Butyl-3-[2-(butylamino)pyrimidin -4-yl]-2-(4-morpholin-4-ylphenyl)pyrazolo[1,5-a]pyridin-7-amine,2-(3-Bromophenyl)-N-cyclopentyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine,2-(3-Bromophenyl)-3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-cyclopropylpyrazolo[1,5-a]pyridin-7-amine,2-(3-Bromophenyl)-N-cyclopropyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine,MethylN-[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]glycinate,5-[(3aS,4S,6aR)-2-Oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl]-N-(4-{7-(butylamino)-3-[2-(butylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-2-yl}phenyl)pentanamide,N-[3-[2-(Cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]butane-1,4-diamine,5-[(3aS,4S,6aR)-2-Oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl]-N-(4-{[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl)pentanamide,3-[2-(Cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine,N,N′-di-tert-butoxycarbonyl-N-(4-{[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl)guanidine,N-(4-{[3-[2-(Cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl)guanidine,N-(4-{[3-[2-(Cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl)methanesulfonamide,N-{[(4-{[3-[2-(Cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl)amino]carbonyl}-4-methylbenzenesulfonamide,4-[(4-{[3-[2-(Cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl)amino]-4-oxobutanoicacid, Diethyl4-{[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butylamidophosphate,4-{[3-[2-(Cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butan-1-ol,Dibenzyl4-{[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butylphosphate,4-{[3-[2-(Cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butylphosphate diammonium salt,2-(3-Azidophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-amine,3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)-N-[2-oxo-2-(1-pyrrolidinyl)ethyl]pyrazolo[1,5-a]pyridin-7-amine,N-(2-{[3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}ethyl)methanesulfonamide,N¹-[3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]-1,2-ethanediamine,N-Cyclopentyl-4-[2-(3-fluorophenyl)-7-(4-morpholinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine,N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-7-amine,2-(3-Chlorophenyl)-N-cyclopropyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine,2-(3-Chlorophenyl)-N-cyclopentyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine,2-(3-Chlorophenyl)-3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-cyclopropylpyrazolo[1,5-a]pyridin-7-amine,N-Cyclopentyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]-2-(3-fluorophenyl)pyrazolo[1,5-a]pyridin-7-amine,4-[2-(3-Chlorophenyl)-7-(4-morpholinyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine,2-(3-Chlorophenyl)-3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-(2-methoxyethyl)pyrazolo[1,5-a]pyridin-7-amine,3-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-cyclopropyl-2-(3-fluorophenyl)pyrazolo[1,5-a]pyridin-7-amine,3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(3-fluorophenyl)-N-(2-methoxyethyl)pyrazolo[1,5-a]pyridin-7-amine,and pharmaceutically acceptable salts thereof.
 12. A pharmaceuticalcomposition comprising a compound according to claim
 1. 13. Thepharmaceutical composition according to claim 12 further comprising apharmaceutically acceptable carrier or diluent.
 14. The pharmaceuticalcomposition according to claim 12 further comprising an antiviral agentselected from the group consisting of aciclovir and valaciclovir.
 15. Amethod for the treatment of a herpes viral infection selected from HSV-1and HSV-2 in an animal, said method comprising administering to theanimal a therapeutically effective amount of a compound according toclaim
 1. 16. A method for the treatment of a condition or diseaseassociated with a herpes viral infection selected from HSV-1 and HSV-2in an animal, comprising administering to the animal a therapeuticallyeffective amount of a compound according to claim
 1. 17. A process forpreparing the compound according to claim 1 wherein R² is selected fromthe group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl,—NR⁷R⁸, —OR⁷, Ay, —OAy, —S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay,Het, —NHHet, —NHR¹⁰Het, —OHet, and —OR¹⁰Het, and R³ and R⁴ are H, saidprocess comprising reacting a compound of formula (IX):

with an amine of formula (X):


18. A process for preparing the compound according to claim 1 wherein R²is selected from the group consisting of alkyl, cycloalkyl, alkenyl,cycloalkenyl, —NR⁷R⁸, —OR⁷, Ay, —OAy, —S(O)_(n)R⁹, —S(O)_(n)Ay,—R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, Het, —NHHet, —NHR¹⁰Het, —OHet, and —OR¹⁰Het; R³ isselected from the group consisting of H, alkyl, cycloalkyl, alkenyl,—R¹⁰OR⁷, —R¹⁰OAy, —NR⁷R⁸ where R⁷ and R⁸ are not H, Ay, —NR⁷Ay where R⁷is not H, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —C(O)R⁷, —C(O)Ay, —CO₂R⁷, —CO₂Ay,—SO₂NHR⁹ and Het; and R⁴ is H, said process comprising reacting acompound of formula (XVI):

with an amine of formula (X):


19. A process for preparing the compound according to claim 1 whereinand R² is selected from the group consisting of alkyl, cycloalkyl,alkenyl, cycloalkenyl, —NR⁷R⁸, —OR⁷, Ay, —OAy, —S(O)_(n)R⁹, —S(O)_(n)Ay,—R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, Het, —NHHet, —NHR¹⁰Het, —OHet, and —OR¹⁰Het, saidprocess comprising the steps of: a) reacting a compound of formula (XX):

 with an amine of formula (X):

 to prepare an intermediate compound; and b) oxidizing the intermediatecompound.
 20. A process for preparing the compound according to claim 1,said process comprising reacting a compound of formula (XXII):

wherein X¹ is chloro, bromo or iodo; with a compound of formula XXIV:

wherein M² is selected from the group consisting of —B(OH)₂, —B(ORa)₂,—B(Ra)₂, —Sn(Ra)₃, Zn-halide, ZnRa, and Mg-halide where Ra is alkyl orcycloalkyl and halide is halo.